Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents

ABSTRACT

Compounds of formula (I): ##STR1## and pharmaceutically acceptable salts thereof are analgesics and anti-inflammatory agents as well having anti-ulcer and 5-lipoxygenase inhibitory activities.

This application is a continuation of U.S. application Ser. No.07/596,578, filed Oct. 10, 1990 (abandoned) which is a continuation ofU.S. application Ser. No. 07/384,725 filed Jul. 25, 1989 (abandoned).

BACKGROUND TO THE INVENTION

The present invention relates to the use of a class of imidazopyrazolederivatives as analgesics and anti-inflammatory agents as well as for anumber of other unexpected and valuable therapeutic purposes,specifically anti-ulcer and 5-lipoxygenase inhibitory activities. Theinvention also provides as new compositions of matter certain novelcompounds falling within this class and provides processes for preparingthese compounds.

The compounds of the present invention have a variety of therapeuticactivities, including an analgesic and anti-inflammatory effect. Anumber of compounds having this type of activity is known, aspirinbeing, perhaps, the best known of these. However, like aspirin, theknown compounds having this type of activity have one majordisadvantage: they tend to cause problems in the digestive tract, andmay ultimately cause ulcers. Most surprisingly, we have found that thecompounds of the present invention, far from causing ulcers, actuallyhave an anti-ulcer activity to an extent that they may have value asanti-ulcer activity to an their own right.

Certain of the compounds employed in the present invention are knownfrom U.S. Pat. Nos. 4,500,630 and No. 4,788,134 and from J. HeterocyclicChem., 10, 411-413 (1973). There is no utility disclosed in the J.Heterocyclic Chem. article, and the U.S. Patents only disclose thecompounds as couplers for photographic materials and as silver salts foruse in photographic materials, respectively. There is absolutely nosuggestion in any of the prior art of which we are aware that thecompounds employed in the present invention have any therapeuticactivity still less that they have the excellent and valuable range ofactivities that we have unexpectedly found, and, so far as we are aware,compounds of this type have never previously been proposed fortherapeutic use.

BRIEF SUMMARY OF INVENTION

In particular, we have found that the compounds of the present inventionhave the following activities: analgesic and anti-inflammatory;anti-ulcer; and 5-lipoxygenase inhibitory activity.

It is an object of the present invention to provide a series ofcompounds having analgesic and anti-inflammatory activities.

It is a further object of the invention to provide compounds havinganti-ulcer activity.

It is a still further object of the invention to provide compoundshaving 5-lipoxygenase inhibitory activity.

The compounds used in the present invention are compounds of formula(I): ##STR2## in which: R¹ and R² are independently selected from thegroup consisting of: hydrogen atoms; C₁ -C₂₅ alkyl groups; substitutedC₁ -C₆ alkyl groups having at least one substituent selected from thegroup consisting of substituents (a), defined below; C₃ -C₈ cycloalkylgroups; C₂ -C₆ alkenyl groups; aralkyl groups in which the or each alkylpart is C₁ -C₄ and the aryl part is C₆ -C₁₀ and is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b), defined below; arylalkenyl groups in which the arylpart is a C₆ -C₁₀ aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b),defined below, and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ arylgroups; C₆ -C₁₀ aryl groups having at least one substituent selectedfrom the group consisting of substituents (b), defined below; aromaticheterocyclic groups which have from 5 to 8 ring atoms of which from 1 to3 are hetero-atoms selected from the group consisting of nitrogen,oxygen and sulfur hetero-atoms, said group being unsubstituted or havingat least one substituent selected from the group consisting ofsubstituents (b), defined below, and being monocyclic or being fused toa benzene ring; cyano groups; and halogen atoms;

R³ represents: a hydrogen atom; a C₁ -C₂₅ alkyl group; a substituted C₁-C₆ alkyl group having at least one substituent selected from the groupconsisting of substituents (a), defined below; an aralkyl group in whichthe or each alkyl part is C₁ -C₄ and the aryl part is C₆ -C₁₀ and isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b), defined below; a C₁ -C₆ aliphaticcarboxylic acyl group; or an aromatic carboxylic acyl group in which thearyl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (b), defined below;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₂₅ alkyl groups; substituted C₁ -C₆ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a), defined below; C₃ -C₈ cycloalkyl groups; C₂ -C₆alkenyl groups; aralkyl groups in which the alkyl part is C₁ -C₄ and theor each aryl part is C₆ -C₁₀ and is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b),defined below; arylalkenyl groups in which the aryl part is a C₆ -C₁₀aryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (b), defined below,and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b), defined below; and aromatic heterocyclicgroups which have from 5 to 8 ring atoms of which from 1 to 3 arehetero-atoms selected from the group consisting of nitrogen, oxygen andsulfur hetero-atoms, said group being unsubstituted or having at leastone substituent selected from the group consisting of substituents (b),defined below, and being monocyclic or being fused to a benzene ring;

substituents (a):

hydroxy groups, halogen atoms, carboxy groups, cyano groups, C₂ -C₇alkoxycarbonyl groups and aromatic heterocyclic groups which have from 5to 8 ring atoms of which from 1 to 3 are hetero-atoms selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, said groupbeing unsubstituted or having at least one substituent selected from thegroup consisting of substituents (b), defined below, and beingmonocyclic or being fused to a benzene ring;

substituents (b):

C₁ -C₆ alkyl groups; halogen atoms; C₁ -C₆ alkoxy groups; aryloxy groupsin which the aryl part is an unsubstituted C₆ -C₁₀ carbocyclic arylgroup; aralkyloxy groups in which the alkyl part is C₁ -C₄ and the oreach aryl part is C₆ -C₁₀ and is unsubstituted; C₁ -C₆ aliphaticcarboxylic acyl groups; aromatic carboxylic acyl groups in which thearyl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting of C₁-C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₆aliphatic carboxylic acyloxy groups; aromatic carboxylic acyloxy groupsin which the aryl part is a C₆ -C₁₀ carbocyclic aryl group which isunsubstituted or has at least one substituent selected from the groupconsisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogenatoms; amino groups; C₁ -C₄ alkylamino groups; dialkylamino groups inwhich each alkyl part is C₁ -C₄ ; C₁ -C₆ aliphatic carboxylic acylaminogroups; aromatic carboxylic acylamino groups in which the aryl part is aC₆ -C₁₀ carbocyclic aryl group which is unsubstituted or has at leastone substituent selected from the group consisting of C₁ -C₄ alkylgroups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₄ haloalkyl groups;carbamoyl groups; alkylcarbamoyl and dialkylcarbamoyl groups in whichthe or each alkyl group is C₁ -C₄ ; carboxy groups; hydroxy groups;cyano groups; and C₂ -C₇ alkoxycarbonyl groups;

and pharmaceutically acceptable salts thereof.

Of these, the compounds are new and are claimed per se except those inwhich R¹ represents a hydrogen atom and R² represents an unsubstitutedalkyl group or an aryl group, or in which R¹ represents a halogen atomand R² represents a hydrogen atom, an unsubstituted alkyl group or acycloalkyl group, or in which R¹ represents an unsubstituted alkyl groupand R² represents an unsubstituted alkyl group.

The invention also provides a method for the treatment or prophylaxis ofa disease or disorder selected from the group consisting of pain,inflammation and ulcers, by the administration to a mammal sufferingfrom said disease or disorder of an effective amount of an activecompound, wherein said active compound is selected from the groupconsisting of compounds of formula (I) and pharmaceutically acceptablesalts thereof.

The invention still further provides a method of relieving oralleviating allergic reactions by the administration to a mammalsuffering from said allergic reaction of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of compounds of formula (I) and pharmaceuticallyacceptable salts thereof.

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of pain, inflammation, ulcers or allergicreactions, which composition comprises an effective amount of an activecompound in admixture with a pharmaceutically acceptable carrier ordiluent, wherein said active compound is selected from the groupconsisting of compounds of formula (I) and pharmaceutically acceptablesalts thereof.

The invention also provides processes for the preparation of thecompounds of the present invention, which are described in greaterdetail hereafter.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the present invention, where R¹, R², R³, R⁴ or R⁵represents an alkyl group, this may be a straight or branched chainalkyl group containing from 1 to 25 carbon atoms, preferably from 1 to 6carbon atoms, and more preferably from 1 to 4 carbon atoms, and examplesinclude the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl,2-methylbutyl, hexyl, isohexyl, 2-methylpentyl, hexyl, isohexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, heptyl, 1-methylhexyl,2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl,5-methylheptyl, 2-ethylhexyl, 2-ethyl-3-methylpentyl,3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl, 7-methyloctyl,4-ethylheptyl, 3-ethyl-2-methylhexyl, 2-ethyl-1-methylhexyl, decyl,2-methylnonyl, 8-methylnonyl, 5-ethyloctyl, 3-ethyl-2-methylheptyl,3,3-diethylhexyl, undecyl, 2-methyldecyl, 9-methyldecyl, 4-ethylnonyl,3,5-dimethylnonyl, 3-propyloctyl, 5-ethyl-4 -methyloctyl, dodecyl,1-methylundecyl, 10-methylundecyl, 3-ethyldecyl, 5-propylnonyl,3,5-diethyloctyl, tridecyl, 11-methyldodecyl, 7-ethylundecyl,4-propyldecyl, 5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl,12-methyltridecyl, 8-ethyldodecyl, 6-propylundecyl, 4-butyldecyl,2-pentylnonyl, pentadecyl, 13-methyltetradecyl, 10-ethyltridecyl,7-propyldodecyl, 5-ethyl-3-methyldodecyl, 4-pentyldecyl, hexadecyl,14-methylpentadecyl, 6-ethyltetradecyl, 4-propyltridecyl,2-butyldodecyl, heptadecyl, 15-methylhexadecyl, 7-ethylpentadecyl,3-propyltetradecyl, 5-pentyldodecyl, octadecyl, 16-methylheptadecyl,5-propylpentadecyl, nonadecyl, 17-methyloctadecyl, 4-ethylheptadecyl,icosyl, 18-methylnonadecyl, 3-ethyloctadecyl, henicosyl, docosyl,tricosyl, tetracosyl and pentacosyl groups. Of these, we generallyprefer the methyl, ethyl, propyl, butyl, pentyl, isopentyl, hexyl,isohexyl, heptyl, octyl, nonyl, undecyl, tridecyl, pentadecyl,heptadecyl, nonadecyl and pentacosyl groups, of which the methyl, ethyl,propyl and butyl groups are more preferred. In the case of R¹ and R²,the methyl and ethyl groups are generally the most preferred alkylgroups where the compound is for analgesic, anti-inflammatory andanti-ulcer use, and C₄ -C₁₁ alkyl groups are generally the mostpreferred where the compound is for use as an inhibitor of5-lipoxygenase.

Where R¹, R², R³, R⁴ or R⁵ represents a substituted alkyl group, thishas at least one substituent selected from the group consisting ofsubstituents (a), defined above and exemplified below. Examples of thealkyl group are the C₁ -C₆ groups of those given as examples above forunsubstituted alkyl groups. There is no restriction, in principle, onthe number of substituents (a) which may be present on any alkyl grouprepresented by R¹, R², R³, R⁴ or R⁵, except such as may be imposed bythe number of substitutable positions and, possibly, by stericconstraints. In general, the maximum preferred number of substituents onany alkyl group is 3, but this may be exceeded in any specific case.

Examples of the groups and atoms which may be included withinsubstituents (a) include:

the hydroxy, carboxy and cyano groups;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms;

C₂ -C₇ alkoxycarbonyl groups (i.e. the alkoxy part has from 1 to 6carbon atoms), such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl,t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl,neopentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl andisohexyloxycarbonyl groups;

aromatic heterocyclic groups which have from 5 to 8 ring atoms of whichfrom 1 to 3 are hetero-atoms selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said group being unsubstitutedor having at least one substituent selected from the group consisting ofsubstituents (b), defined and exemplified below, and being monocyclic orbeing fused to a benzene ring; such substituents and the substitutedgroups derived from them are discussed in more detail hereafter.

Examples of substituted alkyl groups include: groups having a hydroxysubstituent, such as the hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyland 2-hydroxypropyl groups; groups having at least one halogensubstitueny, such as the fluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl,6-fluorohexyl, chloromethyl, trichloromethyl, 2-chloroethyl,2,2,2-trichloroethyl, 3-chloropropyl, 4-chlorobutyl, 5-chloropentyl,6-chlorohexyl, iodomethyl, 2-iodoethyl, 3-iodopropyl, 4-iodobutyl,5-iodopentyl, 6-iodohexyl, bromomethyl, tribromomethyl, 2-bromoethyl,2,2,2-tribromoethyl, 3-bromopropyl, 4-bromobutyl, 5-bromopentyl and6-bromohexyl groups; groups having a cyano substituent, such as thecyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl,4-cyanobutyl, 5-cyanopentyl and 6-cyanohexyl groups; groups having acarboxy substituent, such as the carboxymethyl, 2-carboxyethyl,1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl and6-carboxyhexyl groups; and groups having an alkoxycarbonyl substituent,such as the methoxycarbonylmethyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl,3-propoxycarbonylbutyl, 5-methoxycarbonylpentyl,2-propoxycarbonylpentyl, 5-t-butoxycarbonylpentyl,6-methoxycarbonylhexyl and 6-ethoxycarbonylhexyl groups.

Where R¹, R², R⁴ or R⁵ represents a cycloalkyl group, this has from 3 to8 ring carbon atoms, and examples include the cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, of which thecyclopropyl, cyclopentyl and cyclohexyl groups are preferred.

Where R¹, R², R⁴ or R⁵ represents an alkenyl group, this has from 2 to6, preferably 3 or 4, carbon atoms and may be a straight or branchedchain group. Examples include the vinyl, allyl, 1-propenyl, 2-butenyl,1-butenyl, 2-methylallyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenylgroups, of which the allyl, 2-butenyl and 2-methylallyl groups arepreferred.

Where R¹, R², R³, R⁴ or R⁵ represents an aralkyl group, the alkyl partis C₁ -C₄ and the or each aryl part is C₆ -C₁₀ and is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (b), defined and exemplified below. The number of arylgroups is normally from 1 to 3, although this is not critical. Examplesof such alkyl groups include those alkyl groups having from 1 to 4carbon atoms and exemplified above in relation to the alkyl groups thatmay be represented by R¹ etc. Examples of the aryl groups include thephenyl, 1-naphthyl and 2-naphthyl groups, and these may be substitutedor unsubstituted. Preferred unsubstituted aralkyl groups include thebenzyl, phenethyl, 1-phenylethyl, benzhydryl, triphenylmethyl,2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and2-naphthylmethyl groups. Such groups may also have at least one, andpreferably from 1 to 3, of substituents (b), defined and exemplifiedbelow.

Examples of substituents (b) include:

C₁ -C₆ alkyl groups, such as the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,t-pentyl, 2-methylbutyl, hexyl and isohexyl groups;

halogen atoms, especially the chlorine, fluorine, bromine and iodineatoms;

C₁ -C₆ alkoxy groups, such as the methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy,neopentyloxy, t-pentyloxy, 2-methylbutoxy, hexyloxy and isohexyloxygroups;

aryloxy groups in which the aryl part is an unsubstituted C₆ -C₁₀carbocyclic aryl group, such as the phenoxy, 1-naphthyloxy and2-naphthyloxy groups;

aralkyloxy groups in which the alkyl part is C₁ -C₄ and the aryl part isC₆ -C₁₀ and is unsubstituted, such as the benzyloxy, phenethyloxy,1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-naphthylmethoxy and2-naphthylmethoxy groups;

C₁ -C₆ aliphatic carboxylic acyl groups, such as the formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,acryloyl, methacryloyl, propioloyl, crotonoyl and isocrotonoyl groups;

aromatic carboxylic acyl groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms, such as the benzoyl, naphthoyl,toluoyl (c-, m- or p-), 2,4,6-trimethylbenzoyl, chlorobenzoyl (o-, m- orp-) and methoxybenzoyl (o-, m- or p-) groups;

C₁ -C₆ aliphatic carboxylic acyloxy groups, such as the formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy,propioloyloxy, crotonoyloxy and isocrotonoyloxy groups;

aromatic carboxylic acyloxy groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms, such as the benzoyloxy,naphthoyloxy, toluoyloxy (o-, m- or p-), 2,4,6-trimethylbenzoyloxy,chlorobenzoyloxy (o-, m- or p-) and methoxybenzoyloxy (o-, m- or p-)groups;

amino groups;

C₁ -C₄ alkylamino groups and dialkylamino groups in which each alkylpart is C₁ -C₄, such as the methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino,dimethylamino, diethylamino, dipropylamino, dibutylamino,methylethylamino, methylbutylamino and ethylbutylamino groups;

C₁ -C₆ aliphatic carboxylic acylamino groups, such as the formylamino,acetylamino, propionylamino, butyrylamino, isobutyrylamino,valerylamino, isovalerylamino, pivaloylamino, hexanoylamino,acryloylamino, methacryloylamino, propioloylamino, crotonoylamino andisocrotonoylamino groups;

aromatic carboxylic acylamino groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms, such as the benzoylamino,naphthoylamino, toluoylamino (o-, m- or p-),2,4,6-trimethylbenzoylamino, chlorobenzoylamino (o-, m- or p-) andmethaminobenzoylamino (o-, m- or p-) groups;

C₁ -C₄ haloalkyl groups, such as the trifluoromethyl,2,2,2-trichloroethyl, 2-haloethyl (e.g. 2-chloroethyl, 2-fluoroethyl,2-bromoethyl or 2-iodoethyl), 2,2-dibromoethyl, 2,2,2-tribromoethyl,4-chlorobutyl, 4-bromobutyl and 4-fluorobutyl groups; carbamoyl groups;

alkylcarbamoyl and dialkylcarbamoyl groups in which the or each alkylgroup is C₁ -C₄, such as the methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,sec-butylcarbamoyl, t-butylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl,methylethylcarbamoyl, methylbutylcarbamoyl and ethylbutylcarbamoylgroups;

carboxy groups; and

C₂ -C₇ alkoxycarbonyl groups (i.e. the alkoxy part has from 1 to 6,preferably from 1 to 4, carbon atoms), such as the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl,hexyloxycarbonyl and isohexyloxycarbonyl groups.

Where R¹, R², R⁴ or R⁵ represents an arylalkenyl group, the aryl part isa C₆ -C₁₀ aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b),defined and exemplified above, and the alkenyl part is a C₂ -C₃ alkenylgroup. Examples of aryl groups are as given in relation to the arylgroups forming part of an aralkyl group. Examples of alkenyl groupsinclude the vinyl, 1-propenyl and 2-propenyl groups, and the aryl groupmay be a substituent on any carbon atom of these alkenyl groups.Examples of such arylalkenyl groups include the styryl, α-methylstyryl,cinnamyl, 3-(1-naphthyl)-2-propenyl and 3-phenyl-1-propenyl groups andsuch groups having on the aryl part at least one substituent selectedfrom the group consisting of substituents (b).

Where R¹, R², R⁴ or R⁵ represents an aryl group, this has from 6 to 10ring carbon atoms and may be unsubstituted or may have at least onesubstituent selected from the group consisting of substituents (b),defined and exemplified above. Preferred unsubstituted aryl groupsinclude the phenyl, 1-naphthyl and 2-naphthyl groups. Preferredsubstituents are as exemplified above. Preferred examples of substitutedand unsubstituted groups include: the unsubstituted groups, such as thephenyl, 2-naphthyl and 1-naphthyl groups; the halogen-substitutedgroups, such as the p-fluorophenyl, o-fluorophenyl, m-fluorophenyl,p-bromophenyl, m-bromophenyl, o-chlorophenyl, p-chlorophenyl,m-chlorophenyl and 3,4-dichlorophenyl groups; the haloalkyl-substitutedgroups, such as the p-trifluoromethylphenyl, m-trifluoromethylphenyl ando-trifluoromethylphenyl groups; the alkyl-substituted groups, such asthe p-tolyl, m-tolyl and o-tolyl groups; the alkoxy-substituted groups,such as the p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl and3,4-dimethoxyphenyl groups; the amino-substituted groups, such as thep-aminophenyl group; the aryloxy-substituted groups, such as thep-phenoxyphenyl group; the aralkyloxy-substituted groups, such as thep-benzyloxyphenyl, m-benzyloxyphenyl and o-benzyloxyphenyl groups; thehydroxy-substituted groups, such as the p-hydroxyphenyl, o-hydroxyphenyland m-hydroxyphenyl groups; the cyano-substituted groups, such as thep-cyanophenyl group; the acyl-substituted groups, such as thep-benzoylphenyl group; the carboxy-substituted groups, such as thep-carboxyphenyl group; the carbamoyl-substituted groups, such as thep-carbamoylphenyl group; and the alkoxycarbonyl-substituted groups, suchas the p-methoxycarbonylphenyl and p-ethoxycarbonylphenyl groups.

Where R¹, R², R⁴ or R⁵ or substituent (a) represents an aromaticheterocyclic group, this has from 5 to 8, preferably 5 or 6, ring atomsof which from 1 to 3 are hetero-atoms selected from the group consistingof nitrogen, oxygen and sulfur hetero-atoms. More preferably, theheterocyclic group has from 1 to 3 hetero-atoms, of which 0 or from 1 to3 may be nitrogen atoms and 0, 1 or 2 may be sulfur and/or oxygen atoms(provided, of course, that the total does not exceed 3). An aromaticheterocyclic group is, a heterocyclic group having an aromaticarrangement of double bonds. The group may be unsubstituted or may haveat least one substituent selected from the group consisting ofsubstituents (b), defined below, and it may be monocyclic or it may befused to a benzene ring. Examples of unsubstituted heterocyclic groupsinclude the thienyl (e.g. 2-thienyl or 3-thienyl), furyl (e.g. 2-furyl),pyranyl, pyrrolyl, imidazolyl, pyrazolyl (e.g. 3-pyrazolyl), thiazolyl,isothiazolyl, triazolyl, oxazolyl, isoxazolyl, pyridyl (e.g. 2-pyridyl,3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl (e.g. piperidino and 4-piperidyl), piperazinyl,morpholinyl, thiomorpholinyl, azepinyl, azocinyl, triazocinyl,benzofuranyl, isobenzofuranyl, chromenyl, indolyl, isoindolyl, quinolyl,isoquinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,chromanyl, isochromanyl, indolinyl and isoindolinyl groups. Examples ofsuch substituted heterocyclic groups include the 6-methyl-3-pyridyl,2,6-dichloro-4-pyridyl, 2-methoxy-3-pyridyl, 6-methyl-2-pyridyl,6-chloro-3-pyridyl, 6-(trifluoromethyl)-3-pyridyl, 5-chloro-2-pyridyl,5-(trifluoromethyl)-2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl,5-(trifluoromethyl)-2-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl,5-chloro-2-thienyl, 1-methyl-2-pyrrolyl, 1,5-dimethyl-2-pyrrolyl,3,5-dimethyl-2-pyrrolyl, 4-methyl-5-imidazolyl, 4-methyl-5-oxazolyl,4-pyrazolyl, 5-methyl-4-pyrazolyl, 1-methyl-2-indolyl,5-methoxy-2-indolyl, 5-chloro-2-indolyl, isoquinolyl (e.g.1-isoquinolyl), and quinolyl (e.g. 2-quinolyl) groups.

Where R¹, R², R⁴ or R⁵ represents a heterocyclic-substituted alkylgroup, the heterocyclic part may be any one of the heterocyclic groupsdefined and exemplified above, and the alkyl part may be any one of thealkyl groups having from 1 to 6 carbon atoms referred to above,preferably a C₁ or C₂ group, i.e. a methyl or ethyl group. Specificexamples of such heterocyclic-substituted alkyl groups include thefurfuryl, 2-(2-furyl)ethyl, 2-thenyl, 2-(2-thienyl)ethyl,3-(2-thienyl)propyl, 2-imidazolylmethyl, 2-thiazolylmethyl,2-oxazolylmethyl, 5-isoxazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,2-(3-pyridyl)ethyl, 3-(3-pyridyl)propyl and 3-indolylmethyl groups,where the heterocyclic part may be unsubstituted or may have at leastone substituent selected from the group consisting of substituents (b),defined and exemplified above.

Where R³ represents an aliphatic carboxylic acyl group, this has from 1to 6 carbon atoms. The acyl group may have a saturated or unsaturatedcarbon chain. In the case of a saturated carbon chain, the group is a C₁-C₆ alkanoyl group, preferably a C₂ -C₄ alkanoyl group; in the case ofan unsaturated carbon chain, the group is a C₃ -C₆ alkenoyl or alkynoylgroup, preferably an alkenoyl group, and it may have one or morecarbon-carbon double or triple bonds. Examples of such aliphaticcarboxylic acyl groups include the acetyl, propionyl, butyryl,isobutyryl, 2-methylpropionyl, pentanoyl, 2-methylbutyryl, pivaloyl,valeryl, isovaleryl, hexanoyl, 2-methylpentanoyl, 3-methylpentanoyl,4-methylpentanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl andisocrotonoyl groups.

Where R³ represents an aromatic carboxylic acyl group, the aryl part ofthe group is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (b), defined and exemplified above. Examples of such groupsinclude the benzoyl, 1-naphthoyl and 2-naphthoyl groups, as well as suchgroups having one or more of the substituents defined above, such as theo-, m- or p-toluoyl, o-, m- or p-anisoyl, and o-, m- or p-chlorobenzoylgroups.

In general, where substituents are referred to above, there is norestriction on the number of such substituents, except, as specificallyexplained in relation to substituents on aryl groups, those that mightarise as a result of the number of substitutable positions on the groupbearing the substituent(s), and possibly also steric constraints.Although the exact number of substituents permissible may, therefore,vary in a manner well known to those skilled in the art, as a generalrule, from 1 to 3 such substituents are preferred, except whereotherwise indicated herein.

Preferred classes of compounds of the present invention consist of:

(A) those compounds of formula (I) in which:

R¹ and R² are independently selected from the group consisting of:hydrogen atoms; C₁ -C₁₁ alkyl groups; substituted C₁ -C₆ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a¹), defined below; C₃ -C₆ cycloalkyl groups; C₂ -C₆alkenyl groups; aralkyl groups in which the alkyl part is C₁ -C₄ and thearyl part is a phenyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b¹),defined below; phenylalkenyl groups in which the phenyl part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below, and the alkenyl part isC₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀ aryl groups having at leastone substituent selected from the group consisting of substituents (b¹),defined below; aromatic heterocyclic groups which have 5 or 6 ring atomsof which from 1 to 3 are hetero-atoms selected from the group consistingof nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b¹), defined below, and being monocyclic orbeing fused to a benzene ring; and halogen atoms;

(B) those compounds of formula (I) in which:

R³ represents a hydrogen atom; a C₁ -C₁₁ alkyl group; a substituted C₁-C₆ alkyl group having at least one substituent selected from the groupconsisting of substituents (a¹), defined below; an aralkyl group inwhich the alkyl part is C₁ -C₄ and the aryl part is a phenyl group whichis unsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below; a C₁ -C₆ aliphaticcarboxylic acyl group; or a benzoyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b¹), defined below;

(C) those compounds of formula (I) in which:

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₁₁ alkyl groups; substituted C₁ -C₆ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a¹), defined below; C₃ -C₆ cycloalkyl groups; C₂ -C₆alkenyl groups; aralkyl groups in which the alkyl part is C₁ -C₄ and thearyl part is a phenyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b¹),defined below; phenylalkenyl groups in which the phenyl part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below, and the alkenyl part isC₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀ aryl groups having at leastone substituent selected from the group consisting of substituents (b¹),defined below; and aromatic heterocyclic groups which have 5 or 6 ringatoms of which from 1 to 3 are hetero-atoms selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b¹), defined below, and being monocyclic orbeing fused to a benzene ring;

substituents (a¹):

hydroxy groups, halogen atoms, carboxy groups, cyano groups, C₂ -C₄alkoxycarbonyl groups and aromatic heterocyclic groups which have 5 or 6ring atoms of which from 1 to 3 are hetero-atoms selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b¹), defined below, and being monocyclic orbeing fused to a benzene ring;

substituents (b¹):

C₁ -C₄ alkyl groups; halogen atoms; C₁ -C₄ alkoxy groups; phenoxygroups; aralkyloxy groups in which the alkyl part is C₁ -C₄ and the arylpart is an unsubstituted phenyl group; C₂ -C₆ aliphatic carboxylic acylgroups; benzoyl groups which are unsubstituted or have at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₆ aliphatic carboxylicacyloxy groups; benzoyloxy groups which are unsubstituted or have atleast one substituent selected from the group consisting of C₁ -C₄ alkylgroups, C₁ -C₄ alkoxy groups and halogen atoms; amino groups; C₁ -C₄alkylamino groups; dialkylamino groups in which each alkyl part is C₁-C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; benzoylamino groupswhich are unsubstituted or have at least one substituent selected fromthe group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups andhalogen atoms; C₁ -C₄ haloalkyl groups; carbamoyl groups; alkylcarbamoyland dialkylcarbamoyl groups in which the or each alkyl group is C₁ -C₄ ;carboxy groups; and C₂ -C₅ alkoxycarbonyl groups;

and pharmaceutically acceptable salts thereof.

Especially preferred are those compounds in which R¹ and R² are asdefined in (A) above, R³ is as defined in (B) above and R⁴ and R⁵ are asdefined in (C) above.

More preferred compounds of the present invention are those compounds offormula (I) in which:

R¹ and R² are independently selected from the group consisting of:hydrogen atoms; C₁ -C₆ alkyl groups; substituted C₁ -C₄ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a²), defined below; benzyl groups in which the phenyl partis unsubstituted or has at least one substituent selected from the groupconsisting of substituents (b²), defined below; cinnamyl groups; phenylgroups; naphthyl groups; phenyl or naphthyl groups having at least onesubstituent selected from the group consisting of substituents (b²),defined below; aromatic heterocyclic groups which have 5 or 6 ring atomsof which 1 or 2 is a hetero-atom selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said group being unsubstitutedor having at least one substituent selected from the group consisting ofsubstituents (b²), defined below; and halogen atoms;

R³ represents: a hydrogen atom; a C₁ -C₆ alkyl group; a substituted C₁-C₄ alkyl group having at least one substituent selected from the groupconsisting of substituents (a²), defined below; a benzyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b²), defined below; a C₂ -C₄ aliphaticcarboxylic acyl group; or a benzoyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b²), defined below;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₆ alkyl groups; substituted C₁ -C₄ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a²), defined below; benzyl groups which are unsubstitutedor have at least one substituent selected from the group consisting ofsubstituents (b²), defined below; cinnamyl groups; phenyl groups;naphthyl groups; phenyl or naphthyl groups having at least onesubstituent selected from the group consisting of substituents (b²),defined below; and aromatic heterocyclic groups which have 5 or 6 ringatoms of which 1 or 2 is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b²), defined below;

substituents (a²):

hydroxy groups, halogen atoms, cyano groups, carboxy groups, C₂ -C₄alkoxycarbonyl groups and aromatic heterocyclic groups which have 5 or 6ring atoms of which 1 or 2 is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b²), defined below;

substituents (b²):

C₁ -C₄ alkyl groups; halogen atoms; C₁ -C₄ alkoxy groups;trifluoromethyl groups; hydroxy groups; cyano groups; amino groups;carbamoyl groups; phenoxy groups; C₂ -C₆ aliphatic carboxylic acylgroups; benzoyl groups which are unsubstituted or have at least onesubstituent selected from the group consisting of C₁ -C₂ alkyl groups,C₁ -C₂ alkoxy groups and halogen atoms; C₂ -C₄ aliphatic carboxylicacyloxy groups; benzoyloxy groups which are unsubstituted or have atleast one substituent selected from the group consisting of C₁ -C₂ alkylgroups, C₁ -C₂ alkoxy groups and halogen atoms; carboxy groups; and C₂-C₅ alkoxycarbonyl groups;

and pharmaceutically acceptable salts thereof.

A still more preferred class of compounds of the present invention arethose compounds of formula (I) in which:

R¹ represents a hydrogen atom or a C₁ -C₆ alkyl group;

R² represents: a phenyl group; a substituted phenyl group having atleast one substituent selected from the group consisting of substituents(b²), defined above; or an aromatic heterocyclic group which has 5 or 6ring atoms of which 1 is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b²), defined above;

R³ represents: a hydrogen atom; a C₁ -C₄ alkyl group; a substituted C₁-C₄ alkyl group having at least one substituent selected from the groupconsisting of substituents (a²), defined above; a C₂ -C₄ aliphaticcarboxylic acyl group; or a benzoyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b²), defined below;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₆ alkyl groups; substituted C₁ -C₄ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a²), defined above; and aromatic heterocyclic groups whichhave 5 or 6 ring atoms of which 1 is a hetero-atom selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, said groupbeing unsubstituted or having at least one substituent selected from thegroup consisting of substituents (b²), defined above;

and pharmaceutically acceptable salts thereof.

An alternative still more preferred class of compounds of the presentinvention are those compounds of formula (I) in which:

R¹ represents: a phenyl group; a substituted phenyl group having atleast one substituent selected from the group consisting of substituents(b²), defined above; or an aromatic heterocyclic group which has 5 or 6ring atoms of which 1 is a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or having at least one substituent selected from the groupconsisting of substituents (b²), defined above;

R² represents a hydrogen atom or a C₁ -C₆ alkyl group;

R³ represents: a hydrogen atom; a C₁ -C₄ alkyl group; a substituted C₁-C₄ alkyl group having at least one substituent selected from the groupconsisting of substituents (a²), defined above; a C₂ -C₄ aliphaticcarboxylic acyl group; or a benzoyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b²), defined below;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₆ alkyl groups; substituted C₁ -C₄ alkyl groupshaving at least one substituent selected from the group consisting ofsubstituents (a²), defined above; and aromatic heterocyclic groups whichhave 5 or 6 ring atoms of which 1 is a hetero-atom selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, said groupbeing unsubstituted or having at least one substituent selected from thegroup consisting of substituents (b²), defined above;

and pharmaceutically acceptable salts thereof.

One most preferred class of compounds of the present invention are thosecompounds of formula (I) in which:

R¹ represents a hydrogen atom or a methyl or ethyl group;

R² represents: phenyl group; a substituted phenyl group having at leastone substituent selected from the group consisting of methyl groups,chlorine atoms, trifluoromethyl groups and methoxy groups; a thienylgroup; a furyl group; or a thienyl or furyl group having at least onesubstituent selected from the group consisting of methyl groups, methoxygroups, chlorine atoms and trifluoromethyl groups;

R³ represents: a hydrogen atom; a C₁ -C₂ alkyl group; a C₂ -C₄ aliphaticcarboxylic acyl group; a benzyl group; a cyanomethyl group; a (C₁ -C₄alkoxy)carbonylmethyl group; or a benzoyl group;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₂ alkyl groups; and substituted C₁ -C₂ alkyl groupshaving at least one substituent selected from the group consisting of C₂-C₃ alkoxycarbonyl groups;

and pharmaceutically acceptable salts thereof.

Another most preferred class of compounds of the present invention arethose compounds of formula (I) in which:

R¹ represents: a phenyl group; a substituted phenyl group having atleast one substituent selected from the group consisting of methylgroups, chlorine atoms, trifluoromethyl groups and methoxy groups; athienyl group; a furyl group; or a thienyl or furyl group having atleast one substituent selected from the group consisting of methylgroups, methoxy groups, chlorine atoms and trifluoromethyl groups;

R² represents a hydrogen atom or a methyl or ethyl group;

R³ represents: a hydrogen atom; a C₁ -C₂ alkyl group; a benzyl group; acyanomethyl group; a (C₁ -C₄ alkoxy)carbonylmethyl group; a C₂ -C₄aliphatic carboxylic acyl group; or a benzoyl group;

R⁴ and R⁵ are independently selected from the group consisting of:hydrogen atoms; C₁ -C₂ alkyl groups; and substituted C₁ -C₂ alkyl groupshaving at least one substituent selected from the group consisting of C₂-C₃ alkoxycarbonyl groups;

and pharmaceutically acceptable salts thereof.

The compounds of the present invention necessarily contain basic groupsand can, therefore, form acid addition salts. The nature of such saltsand of the acids employed to form them is not critical to the invention,provided that, where the compound is intended for use therapeutically,the salt is pharmaceutically acceptable, which, as is well known, meansthat it does not have a lower (or significantly lower) activity or ahigher (or significantly higher) toxicity than the free base. However,where the compound is intended for other uses, e.g. as an intermediatein the preparation of other compounds, even this limitation does notapply.

Examples of acids which can form such salts include: inorganic acids,such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoricacid, sulfuric acid or nitric acid; organic sulfonic acids, such asmethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid; and organic carboxylic acids, such as oxalicacid, tartaric acid, citric acid, maleic acid, malonic acid, succinicacid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lacticacid, gluconic acid and malic acid.

Specific examples of compounds of the present invention are thosecompounds of formula (I) in which R¹, R², R³, R⁴ and R⁵ are as definedin the following Table 1. In the Table, the following abbreviations areused:

    ______________________________________                                        Ac                acetyl                                                      All               allyl                                                       Boz               benzoyl                                                     Bu                butyl                                                       Bz                benzyl                                                      Car               carbamoyl                                                   Et                ethyl                                                       Etc               ethoxycarbonyl                                              Fur               furyl                                                       Hdc               hexadecyl                                                   Hpdc              heptadecyl                                                  Hx                hexyl                                                       Imid              imidazolyl                                                  Ind               indolyl                                                     Me                methyl                                                      Mec               methoxycarbonyl                                             Ndc               nonadecyl                                                   Nn                nonyl                                                       Np                naphthyl                                                    Oc                octyl                                                       Oxa               oxazolyl                                                    Pdc               pentadecyl                                                  Ph                phenyl                                                      Pn                pentyl                                                       .sub.-iPn        isopentyl                                                   Pr                propyl                                                       .sub.-iPr        isopropyl                                                   Pyaz              pyrazolyl                                                   Pyr               pyridyl                                                     Pyrr              pyrrolyl                                                     .sub.-iQuin      isoquinolyl                                                 Tdc               tridecyl                                                    Tfm               trifluoromethyl                                             Then              thenyl                                                      Thi               thienyl                                                     Udc               undecyl                                                     ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    Cpd                                                                           No. R.sup.1 R.sup.2 R.sup.3                                                                             R.sup.4                                                                             R.sup.5                                       __________________________________________________________________________    1   H       Ph      H     H     H                                             2   H        -p-FPh H     H     H                                             3   H        -p-TfmPh                                                                             H     H     H                                             4   H        .sub.--m-TfmPh                                                                       H     H     H                                             5   H        -o-TfmPh                                                                             H     H     H                                             6   H        -p-MePh                                                                              H     H     H                                             7   H        .sub.--m-MePh                                                                        H     H     H                                             8   H        -o-MePh                                                                              H     H     H                                             9   H        -p-MeOPh                                                                             H     H     H                                             10  H        .sub.--m-MeOPh                                                                       H     H     H                                             11  H        -o-MeOPh                                                                             H     H     H                                             12  H        -p-BrPh                                                                              H     H     H                                             13  H        .sub.--m-BrPh                                                                        H     H     H                                             14  H        -o-ClPh                                                                              H     H     H                                             15  H        -p-ClPh                                                                              H     H     H                                             16  H        .sub.--m-ClPh                                                                        H     H     H                                             17  H       3,4-diClPh                                                                            H     H     H                                             18  Me      Ph      H     H     H                                             19  Et      Ph      H     H     H                                             20   .sub.-iPr                                                                            Ph      H     H     H                                             21  Pr      Ph      H     H     H                                             22  Bu      Ph      H     H     H                                             23  F.sub.3 CCH.sub.2 --                                                                  Ph      H     H     H                                             24  All     Ph      H     H     H                                             25  Bz      Ph      H     H     H                                             26  Ph      Ph      H     H     H                                             27  Me       -p-ClPh                                                                              H     H     H                                             28  Et       -p-ClPh                                                                              H     H     H                                             29  H       Bz      H     H     H                                             30  H       Ph      Me    H     H                                             31  H        .sub.--m-TfmPh                                                                       Et    H     H                                             32  H       Ph      Ac    H     H                                             33  H        -p-ClPh                                                                              Boz   H     H                                             34  H       Ph      H     Me    H                                             35  H       Ph      H     H     Me                                            36  H       Ph      H     EtcCH.sub.2 --                                                                      H                                             37  H       Ph      H     H     EtcCH.sub.2 --                                38  Me      Ph      H     EtcCH.sub.2 --                                                                      H                                             39  HOCH.sub.2 --                                                                         Ph      H     H     H                                             40  Br      Ph      H     H     H                                             41  Ph      H       H     H     H                                             42  Me       -p-TfmPh                                                                             H     H     H                                             43  All      -p-TfmPh                                                                             H     H     H                                             44  Me       .sub.--m-ClPh                                                                        H     H     H                                             45  F.sub.3 CCH.sub.2 --                                                                   -p-ClPh                                                                              H     H     H                                             46  All      -p-ClPh                                                                              H     H     H                                             47  H       Ph      H     Ph    H                                             48  H       Ph      H     H     Ph                                            49  H       1-Me-2-Ind                                                                            H     H     H                                             50  H       1-Me-2-Pyrr                                                                           H     H     H                                             51  H       1,5-diMe-2-Pyrr                                                                       H     H     H                                             52  H       3,5-diMe-2-Pyrr                                                                       H     H     H                                             53  H       2-Thi   H     H     H                                             54  H       3-Me-2-Thi                                                                            H     H     H                                             55  H       5-Cl-2-Thi                                                                            H     H     H                                             56  H       5-Me-2-Thi                                                                            H     H     H                                             57  Me      2-Thi   H     H     H                                             58  Et      2-Thi   H     H     H                                             59  Ph      2-Thi   H     H     H                                             60  H       2-Fur   H     H     H                                             61  H       5-Me-2-Fur                                                                            H     H     H                                             62  H       2,5-diMe-3-Fur                                                                        H     H     H                                             63  H       2-Pyr   H     H     H                                             64  H       4-Pyr   H     H     H                                             65  H       3-Pyr   H     H     H                                             66  H       6-Me-3-Pyr                                                                            H     H     H                                             67  H       2,6-diCl-4-Pyr                                                                        H     H     H                                             68  H       2-MeO-3-Pyr                                                                           H     H     H                                             69  H       4-Me-5-Oxa                                                                            H     H     H                                             70  H       5-MeO-2-Ind                                                                           H     H     H                                             71  H       5-Cl-2-Ind                                                                            H     H     H                                             72  H       1- .sub.-iQuin                                                                        H     H     H                                             73  H       3-Pyaz  H     H     H                                             74  H       4-Me-5-Imid                                                                           H     H     H                                             75  H       2-Then  H     H     H                                             76  Ph      Me      H     H     H                                             77  Ph      Et      H     H     H                                             78  Ph      Pr      H     H     H                                             79  Ph       .sub.-iPr                                                                            H     H     H                                             80  Ph      Bu      H     H     H                                             81  Ph      H       Me    H     H                                             82  Ph      H       Et    H     H                                             83  Ph      H       Ac    H     H                                             84  Ph      H       Boz   H     H                                             85  Ph      H       H     Me    H                                             86  Ph      H       H     H     Me                                            87  Ph      H       H     EtcCH.sub.2 --                                                                      H                                             88  Ph      H       H     H     EtcCH.sub.2 --                                89  Ph      Me      H     EtcCH.sub.2 --                                                                      H                                             90   -p-TfmPh                                                                             H       H     H     H                                             91   -p-TfmPh                                                                             Me      H     H     H                                             92   .sub.--m-TfmPh                                                                       H       H     H     H                                             93   .sub.--m-TfmPh                                                                       Me      H     H     H                                             94   -o-TfmPh                                                                             H       H     H     H                                             95   -o-TfmPh                                                                             Me      H     H     H                                             96   -p-FPh H       H     H     H                                             97   -p-FPh Me      H     H     H                                             98    -p-BrPh                                                                             H       H     H     H                                             99   -p-BrPh                                                                              Me      H     H     H                                             100  -p-ClPh                                                                              H       H     H     H                                             101  -p-ClPh                                                                              Me      H     H     H                                             102  -p-ClPh                                                                              Et      H     H     H                                             103  .sub.--m-ClPh                                                                        H       H     H     H                                             104  .sub.--m-ClPh                                                                        Me      H     H     H                                             105  -o-ClPh                                                                              H       H     H     H                                             106  -o-ClPh                                                                              Me      H     H     H                                             107 3,4-diClPh                                                                            H       H     H     H                                             108  -p-MePh                                                                              H       H     H     H                                             109  -p-MePh                                                                              Me      H     H     H                                             110  .sub.--m-MePh                                                                        H       H     H     H                                             111  .sub.--m-MePh                                                                        Me      H     H     H                                             112  -o-MePh                                                                              H       H     H     H                                             113  -o-MePh                                                                              Me      H     H     H                                             114  -p-MeOPh                                                                             H       H     H     H                                             115  -p-MeOPh                                                                             Me      H     H     H                                             116  .sub.--m-MeOPh                                                                       H       H     H     H                                             117  .sub.--m-MeOPh                                                                       Me      H     H     H                                             118  -o-MeOPh                                                                             H       H     H     H                                             119  -o-MeOPh                                                                             Me      H     H     H                                             120  -p-NH2Ph                                                                             H       H     H     H                                             121  -p-NH2Ph                                                                             Me      H     H     H                                             122 3,4-diMeOPh                                                                           H       H     H     H                                             123 3,4-diMeOPh                                                                           Me      H     H     H                                             124 2-Np    H       H     H     H                                             125 2-NP    Me      H     H     H                                             126  -p-PhOPh                                                                             H       H     H     H                                             127  -p-PhOPh                                                                             Me      H     H     H                                             128  -p-BzOPh-                                                                            H       H     H     H                                             129  -p-BzOPh-                                                                            Me      H     H     H                                             130  -o-BzOPh-                                                                            H       H     H     H                                             131  -o-BzOPh-                                                                            Me      H     H     H                                             132  -p-HOPh                                                                              H       H     H     H                                             133  -p-HOPh                                                                              Me      H     H     H                                             134  .sub.--m-HOPh                                                                        H       H     H     H                                             135  .sub.--m-HOPh                                                                        Me      H     H     H                                             136  -p-CNPh                                                                              H       H     H     H                                             137  -p-CNPh                                                                              Me      H     H     H                                             138  -p-BozPh                                                                             H       H     H     H                                             139  - p-BozPh                                                                            Me      H     H     H                                             140 2-Thi   H       H     H     H                                             141 2-Thi   Me      H     H     H                                             142 2-Thi   Et      H     H     H                                             143 3-Me-2-Thi                                                                            H       H     H     H                                             144 5-Me-2-Thi                                                                            H       H     H     H                                             145 5-Cl-2-Thi                                                                            H       H     H     H                                             146 2-Fur   Me      H     H     H                                             147 5-Me-2-Fur                                                                            Me      H     H     H                                             148 1-Me-2-Pyrr                                                                           Me      H     H     H                                             149 1,5-diMe-2-Pyrr                                                                       Me      H     H     H                                             150 2-Pyr   H       H     H     H                                             151 2-Pyr   Me      H     H     H                                             152 3-Pyr   Me      H     H     H                                             153 4-Pyr   Me      H     H     H                                             154 6-Me-2-Pyr                                                                            H       H     H     H                                             155 1-Me-2-Ind                                                                            Me      H     H     H                                             156 5-MeO-2-Ind                                                                           Me      H     H     H                                             157 5-Cl-2-Ind                                                                            Me      H     H     H                                             158 4-Me-5-Oxa                                                                            Me      H     H     H                                             159 4-Pyaz  Me      H     H     H                                             160 5-Me-4-Pyaz                                                                           Me      H     H     H                                             161  -p-HOOC-Ph                                                                           H       H     H     H                                             162  -p-EtcPh                                                                             Me      H     H     H                                             163  -p-CarPh                                                                             Me      H     H     H                                             164 H        -p-HOOC-Ph                                                                           H     H     H                                             165 Me       -p-MecPh                                                                             H     H     H                                             166 Me       -p-CarPh                                                                             H     H     H                                             167 3-Thi   H       H     H     H                                             168 3-Thi   Me      H     H     H                                             169 Oc      Ph      H     H     H                                             170 Nn      Ph      H     H     H                                             171 Udc     Ph      H     H     H                                             172 Pdc     2-Thi   H     H     H                                             173 Hdc     2-Thi   H     H     H                                             174  .sub.-iPn                                                                            Ph      H     H     H                                             175 2-MePn  Ph      H     H     H                                             176 1-MeHx  Ph      H     H     H                                             177  .sub.-iPn                                                                            2-Thi   H     H     H                                             178 HPdc     -p-MePh                                                                              H     H     H                                             179 Nn       -p-ClPh                                                                              H     H     H                                             180 Ph       .sub.-iPn                                                                            H     H     H                                             181 Ph      Oc      H     H     H                                             182 Ph      Nn      H     H     H                                             183 Ph      Dc      H     H     H                                             184 Ph      Udc     H     H     H                                             185 Ph      Tdc     H     H     H                                             186 Ph      Pdc     H     H     H                                             187 Ph      HPdc    H     H     H                                             188 Ph      Ndc     H     H     H                                             189 2-Thi    .sub.-iPr                                                                            H     H     H                                             190 H       Ph      EtcCH.sub.2 --                                                                      H     H                                             191 H       Ph      CNCH.sub.2 --                                                                       H     H                                             192 H        -o-HOPh                                                                              H     H     H                                             193 Me       -o-HOPh                                                                              H     H     H                                             194 H         -o-BzOPh                                                                            H     H     H                                             195 Me       -o-BzOPh                                                                             H     H     H                                             196 H        -o-HOPh                                                                              Bz    H     H                                             197 Me       -o-HOPh                                                                              Bz    H     H                                             198 Me       -o-BzOPh                                                                             Bz    H     H                                             199 Me       -p-HOPh                                                                              H     H     H                                             200 Me       -p-BzOPh                                                                             H     H     H                                             201 H        .sub.--m-HOPh                                                                        H     H     H                                             202 Me       .sub.--m-HOPh                                                                        H     H     H                                             203 H        .sub.--m-BzOPh                                                                       H     H     H                                             204 Me       .sub.--m-BzOPh                                                                       H     H     H                                             205 Me      2-NP    H     H     H                                             206 H       Ph      2-EtcEt                                                                             H     H                                             __________________________________________________________________________

Of the compounds listed above, the following are preferred, that is tosay Compounds No. 1, 4, 9, 15, 17, 18, 27, 41, 53, 57, 58, 60, 76, 93,101, 108, 109, 114, 140, 141 and 146, and the more preferred compoundsare:

1. 6-phenyl-1H-imidazo[1,2-b]pyrazole

15. 6-(p-chlorophenyl)-1H-imidazo[1,2-b]pyrazole

18. 7-methyl-6-phenyl-1H-imidazo[1,2-b]pyrazole

41. 7-phenyl-1H-imidazo[1,2-b]pyrazole

53. 6-(2-thienyl)-1H-imidazo[1,2-b]pyrazole

57. 7-methyl-6-(2-thienyl)-1H-imidazo[1,2-b]pyrazole

76. 6-methyl-7-phenyl-1H-imidazo[1,2-b]pyrazole

101. 6-methyl-7-(p-chlorophenyl)-1H-imidazo[1,2-b]pyrazole

108. 7-(p-methylphenyl)-1H-imidazo[1,2-b]pyrazole

140. 7-(2-thienyl)-1H-imidazo[1,2-b]pyrazole

141. 6-methyl-7-(2-thienyl)-1H-imidazo[1,2-b]pyrazole

and pharmaceutically acceptable salts thereof.

The compounds of the present invention can be prepared by a variety ofprocesses of types which are well known in the art for the preparationof this kind of compound. In general terms, the compounds can beprepared by the ring closure of a compound of formula (II): ##STR3## (inwhich R¹, R², R⁴ and R⁵ are as defined above, and the group representedby >C═Y is a carbonyl group or an acetal group) and then, if required,reacting the product with a compound of formula (III):

    R.sup.3' Z                                                 (III)

(in which: R^(3') represents any of the groups defined for R³ other thana hydrogen atom; and Z represents a halogen atom, a C₁ -C₄alkanesulfonyloxy group or an arylsulfonyloxy group).

The compound of formula (II) may be prepared by reacting a pyrazolederivative of formula (IV): ##STR4## (in which R¹ and R² are as definedabove) with a compound of formula (V): ##STR5## (in which: >C═Y, R⁴ andR⁵ are as defined above; and X represents a halogen atom, a C₁ -C₄alkanesulfonyloxy group or an arylsulfonyloxy group).

Examples of the substituents Z and X in the compounds of formulae (III)and (V), respectively, include: halogen atoms, such as the chlorine,bromine and iodine atoms; lower alkanesulfonyloxy groups, such as themethanesulfonyloxy and ethanesulfonyloxy groups; arylsulfonyloxy groups,such as the benzenesulfonyloxy and p-toluenesulfonyloxy groups. Examplesof the acetal group which may be represented by >C═Y include di-(loweralkyl)acetal groups, such as the dimethylacetal and diethylacetalgroups.

Reaction of the pyrazole derivative of formula (IV) with the carbonylcompound or acetal of formula (V) is normally and preferably effected ina solvent. There is no particular restriction on the nature of thesolvent to be employed, provided that it has no adverse effect on thereaction or on the reagents involved. Examples of suitable solventsinclude: halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as methylene chloride and chloroform; aromatichydrocarbons, such as benzene, toluene and xylene; nitriles, such asacetonitrile; and amides, especially fatty acid amides, such asdimethylformamide.

The reaction is effected in the presence of a base, the nature of whichis likewise not critical. Examples of suitable bases include: hydrides,especially alkali metal hydrides, such as sodium hydride; and organicbases, such as triethylamine.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature from 10° C. to around the boiling point of the solvent used.The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents. However, provided that the reaction is effected under thepreferred conditions outlined above, a period of from 1 to 10 hours willusually suffice.

Alternatively, the compound of formula (II) may be prepared by reactinga compound of formula (VI): ##STR6## (in which R¹ and R² are as definedabove) with a compound of formula (VII): ##STR7## (in which R⁴, R⁵ and Yare as defined above). The reaction is normally and preferably effectedin a solvent, the nature of which is not critical, provided that it hasno adverse effect upon the reaction. Examples of suitable solventsinclude: halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as chloroform, methylene chloride and carbontetrachloride; aromatic hydrocarbons, such as benzene, toluene andxylene; alcohols, such as methanol, ethanol and isopropanol; amides,especially fatty acid amides, such as dimethylformamide; and nitriles,such as acetonitrile. The reaction will take place over a wide range oftemperatures, and the precise reaction temperature chosen is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature in the range of from 10° C. to theboiling temperature of the solvent. The time required for the reactionmay likewise vary widely, depending on many factors, notably thereaction temperature and the nature of the reagents. However, in mostcases, a period of from 1 to 20 hours will normally suffice.

After completion of the reaction, the desired compound may be recoveredfrom the reaction mixture by conventional means. For example, thereaction mixture may be poured into water, extracted with an organicsolvent, and, if necessary dried. It may then be freed from the solventby distillation under reduced pressure. If required, it may then befurther purified by conventional techniques, for example the variouschromatography techniques, notably column chromatography.

The resulting compound of formula (II) may then be converted to acompound of formula (I) in which R³ represents a hydrogen atom by a ringclosure reaction. This may be effected by adding at least a catalyticamount of a suitable acid, e.g. an organic sulfonic acid (such asp-toluenesulfonic acid) or a mineral acid (such as hydrochloric acid orsulfuric acid), preferably hydrogen chloride in dioxane. The amount ofacid catalyst may vary widely from a catalytic amount to a large excess,e.g. around 10 equivalents of acid per equivalent of compound of formula(II), in order to accelerate the reaction. The reaction is normally andpreferably effected in an organic solvent, the nature of which is notcritical, provided that it has no adverse effect upon the reaction.Examples of suitable solvents include: aromatic hydrocarbons, such asbenzene, toluene and xylene; ethers, such as dioxane andtetrahydrofuran; and alcohols, such as methanol and ethanol. Thereaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from room temperature to around the boilingpoint of the solvent used. The time required for the reaction maylikewise vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, in most cases, aperiod of from 5 minutes to 2 hours will normally suffice.

After completion of the reaction, the desired compound of formula (Ia)may be recovered from the reaction mixture by conventional means. Forexample, one suitable recovery technique comprises: pouring the reactionmixture into ice-water; making it alkaline by the addition of ammonia orsodium bicarbonate; and then extracting the mixture with an organicsolvent. The desired compound may then be obtained from the extract bystandard techniques. If desired, the resulting compound may be furtherpurified by such conventional techniques as recrystallization or thevarious chromatography techniques, notably column chromatography.##STR8## (in which R¹, R², R⁴ and R⁵ are as defined above).

The compound of formula (Ia) can also be obtained by heating theintermediate compound of formula (II) with PPA (polyphosphoric acid).

A compound of formula (I) in which R³ represents a group other than ahydrogen atom, that is to say a compound of formula (Ib): ##STR9## (inwhich R¹, R², R^(3'), R⁴ and R⁵ are as defined above) may be prepared byreacting a compound of formula (Ia) with a compound of formula (III):

    R.sup.3' Z                                                 (III)

(wherein Z and R^(3') are as defined above) in the presence of a base.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction. Examples of suitable solvents include:halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons,such as methylene chloride, chloroform and carbon tetrachloride;aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles,such as acetonitrile; and amides, especially fatty acid amides, such asdimethylformamide and dimethylamide. The reaction will take place over awide range of temperatures, and the precise reaction temperature chosenis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature in the range of from 0° C. toaround the boiling point of the solvent used. The time required for thereaction may likewise vary widely, depending on many factors, notablythe reaction temperature and the nature of the reagents. However, inmost cases, a period of from 1 to 20 hours will normally suffice.

There is no particular restriction on the nature of the base, providedthat it has no adverse effect on other parts of the molecule. Examplesof suitable bases include: alkali metal hydroxides, such as sodiumhydroxide and potassium hydroxide; alkali metal hydrides, such as sodiumhydride; and organic bases, such as pyridine and triethylamine.

After completion of the reaction, desired compound may be recovered fromthe reaction mixture by conventional means, and the resulting compoundmay further be purified by such conventional techniques asrecrystallization or the various chromatography techniques, notablycolumn chromatography.

The compound of formula (IV) used as the starting material may besynthesized by the method of Takamizawa et al. [Yakugaku Zasshi 84, 1113(1964)].

As is demonstrated by the biological activity data given hereafter, theimidazopyrazole derivatives of formula (I) and salts thereof exhibitexcellent analgesic, anti-inflammatory and anti-allergic activities andthey also exhibit an anti-ulcer effect. They also have a low toxicityand limited side effects. They are, therefore, expected to be of valuein the treatment, alleviation and prophylaxis of a wide variety ofdisorders, for example for improving and treating chronic articularrheumatism, lumbago, neck-shoulder-arm syndrome, etc. They may also beused for the treatment and prophylaxis of allergic reactions. Thecompounds of the present invention are preferably administered aspharmaceutical compositions alone or in admixture with variouspharmaceutically acceptable carriers, diluents or excipients, chosenhaving regard to the desired route of administration. The compounds maybe administered orally or parenterally and suitable formulations includepowders, granules, tablets, injections, suppositories, ointments andplasters. The dosage of the compounds of the invention will vary,depending upon the severity and nature of the disease or disorder, aswell as the route, frequency and period of administration. However, asuitable dose for an adult human would be in the range of from 0.025 to0.3 g, which may be administered in a single dose or in divided doses,e.g. from one to three times per day for oral administration.

The preparation of the compounds of the present invention is furtherillustrated by the following non-limiting Examples 1 to 62. The use ofthese compounds to prepare pharmaceutical preparations is illustrated bythe subsequent Examples 63 and 64. The biological activity of thecompounds of the invention is then illustrated.

EXAMPLE 1 6-(4-Trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazole

1.0 g of 3-amino-5-(trifluoromethylphenyl)pyrazole and 5 ml ofdimethylformamide were slowly added dropwise at room temperature, whilststirring, to 0.15 g of a 55% w/w suspension of sodium hydride in mineraloil, which was itself suspended in 15 ml of dimethylformamide, and theresulting mixture was stirred for one hour at room temperature, afterwhich 1.06 g of 2,2-dimethoxyethyl bromide was added at roomtemperature, whilst stirring. The mixture was then stirred at 70° to 80°C. for 3 hours. At the end of this time, the reaction mixture waspartitioned between ethyl acetate and water. The ethyl acetate layer waswashed with water and with an aqueous solution of sodium chloride, andwas then dried over anhydrous magnesium sulfate. The solvent was thenremoved by evaporation under reduced pressure, to afford 700 mg of theintermediate compound,3-amino-2-dimethoxyethyl-5-(4-trifluoromethylphenyl)pyrazole, as an oil.

A mixture of 700 mg of this intermediate compound and 7.0 g ofpolyphosphoric acid was stirred at 100° C. for 30 minutes, after whichthe reaction mixture was poured into ice-water and neutralized by theaddition of sodium bicarbonate. The mixture was then extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfate,and the solvent was then removed by evaporation under reduced pressure,to afford the title compound as crude crystals. These crude crystal werepurified by silica gel column chromatography using a 1:1 by volumemixture of ethyl acetate and hexane as the eluent, and the product wasthen recrystallized from a mixture of ethyl acetate and hexane to give0.3 g of 6-(4-trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazole as palebrown needle-like crystals, melting at 134° to 135° C.

Elemental analysis: Calculated for C₁₂ H₈ N₃ F₃ : C, 57.37%; H, 3.21%;N, 16.73%; F, 22.69%. Found: C, 58.80%; H, 3.35%; N, 16.79%; F, 22.14%.

EXAMPLES 2 TO 5

The following compounds were synthesized in the same manner as describedin Example 1.

                  TABLE 2                                                         ______________________________________                                        Example       Compound                                                        No.           No.       m.p. (°C.)                                     ______________________________________                                        2             4         134 to 135                                            3             1         187 to 189                                            4             18        198 to 200                                            5             9         201 to 204                                            ______________________________________                                    

EXAMPLE 6 6-(4-Fluorophenyl)-1H-imidazo[1,2-b]pyrazole

2.0 g of 3-amino-5-(4-fluorophenyl)pyrazole and 10 ml ofdimethylformamide were slowly added dropwise at room temperature, whilststirring, to 0.3 g of a 55% w/w suspension of sodium hydride in mineraloil, which was itself suspended in 20 ml of dimethylformamide, and theresulting mixture was then stirred for a further 1 hour at the sametemperature. 2.1 g of 2,2-dimethoxyethyl bromide were then addeddropwise at room temperature, whilst stirring. When the addition wascomplete, the mixture was stirred at 80° to 90° C. for 3 hours. At theend of this time, the reaction mixture was partitioned between ethylacetate and water, and the ethyl acetate layer was washed with water andwith an aqueous solution of sodium chloride. It was then dried overanhydrous magnesium sulfate, and the solvent was removed by evaporationunder reduced pressure, to afford 1.2 g of the intermediate compound3-amino-2-dimethoxyethyl-5-(4-fluorophenyl)pyrazole as an oil.

A mixture of 1.2 g of this intermediate compound, 10 ml of a 4N solutionof hydrogen chloride in dioxane and 5 ml of ethanol was heated underreflux for 30 minutes, after which the solvent components of the mixturewere removed by evaporation under reduced pressure. The residue waspartitioned between ethyl acetate and an aqueous solution of sodiumbicarbonate. The ethyl acetate layer was washed with an aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was then removed by evaporation under reduced pressure, toafford the title compound as crude crystals. These crude crystals werepurified by silica gel column chromatography using a 1:1 by volumemixture of ethyl acetate and hexane as the eluent, and the product wasthen recrystallized from a mixture of ethyl acetate and hexane to give0.5 g of 6-(4-fluorophenyl)-1H-imidazo[1,2-b]pyrazole as pale violetneedle-like crystals, melting at 225° to 227° C.

Elemental analysis: Calculated for C₁₁ H₈ N₃ F: C, 65.67%; H, 4.01%; N,20.88%; F, 9.44%. Found: C, 65.97%; H, 4.25%; N, 20.99%; F, 9.22%.

EXAMPLES 7 TO 19

The following compounds were synthesized in the same manner as describedin Example 6.

                  TABLE 3                                                         ______________________________________                                        Example       Compound                                                        No.           No.       m.p. (°C.)                                     ______________________________________                                         7             6        197 to 200                                             8            15        203 to 205                                             9            42        235 to 237                                            10            19        190 to 193                                            11            20        206 to 208                                            12            22        179 to 180                                            13            25        160 to 163                                            14            29        147 to 149                                            15            23        206 to 208                                            16            24        163 to 165                                            17            17        169 to 172                                            18            48        242 to 245                                            19            12        225 to 227                                            ______________________________________                                    

EXAMPLE 20 6-(2-Thienyl)-1H-imidazo[1,2-b]pyrazole

A solution of 1.0 g of 5-(2-thienyl)-3-aminopyrazole in 5 ml ofdimethylformamide was slowly added dropwise at room temperature, whilststirring, to 0.26 g of a 55% w/w suspension of sodium hydride in mineraloil, which itself was suspended in 15 ml of dimethylformamide. Theresulting mixture was then stirred for 1 hour at room temperature, afterwhich 1.3 g of 2,2-dimethoxyethyl bromide was added, and the mixture wasallowed to react at 50° to 60° C. for 3 hours. At the end of this time,the mixture was partitioned between ethyl acetate and water. The organiclayer was washed with water and dried over anhydrous magnesium sulfate,and then the solvent was removed by evaporation under reduced pressure.The residue was purified by silica gel column chromatography using a 1:1by volume mixture of ethyl acetate and hexane as the eluent, to afford0.9 g of an intermediate compound as an oil.

A mixture of 0.9 g of this intermediate compound, 5 ml of a 4N solutionof hydrogen chloride in dioxane and 3 ml of ethanol was heated underreflux for 10 minutes. The reaction mixture was then poured intoice-water and made basic by the addition of aqueous ammonia. The mixturewas then extracted with ethyl acetate. The extract was washed with anaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was then removed by evaporation under reducedpressure, and the residue was purified by silica gel columnchromatography using a 1:1 by volume mixture of ethyl acetate and hexaneas the eluent. The product was then recrystallized from a mixture ofethyl acetate and hexane, to afford 0.35 g of the title compound ascolorless needle-like crystals melting at 199° to 203° C.

Elemental analysis: Calculated for C₉ H₇ N₃ S C, 57.12%; H, 3.73%; N,22.21%; F, 16.94%. Found: C, 57.09%; H, 3.69%; N, 22.08%; F, 17.05%.

EXAMPLE 21 7-Methyl-6-(2-thienyl)-1H-imidazo[1,2-b]pyrazole

A solution of 1.9 g of 3-amino-4-methyl-5-(2-thienyl)pyrazole in 15 mlof dimethylformamide was slowly added dropwise at room temperature,whilst stirring, to 0.5 g of a 55% w/w suspension of sodium hydride inmineral oil, which itself was suspended in 10 ml of dimethylformamide.The resulting mixture was then stirred for 1 hour at room temperature,after which 2.0 g of 2,2-dimethoxyethyl bromide were added, and themixture was allowed to react at 60° to 70° C. for 4 hours. At the end ofthis time, the resulting mixture was partitioned between ethyl acetateand water. The organic layer was washed with water and dried overanhydrous magnesium sulfate, after which the solvent was removed byevaporation under reduced pressure. The residue was purified by silicagel column chromatography using a 1:1 by volume mixture of ethyl acetateand hexane as the eluent, to afford 0.4 g of an intermediate compound asan oil.

A mixture of 0.4 g of this intermediate compound, 4 ml of a 4N solutionof hydrogen chloride in dioxane and 1.5 ml of ethanol was heated underreflux for 10 minutes, after which the reaction mixture was poured intoice water and made basic by the addition of aqueous ammonia. The mixturewas then extracted with ethyl acetate. The extract was washed with anaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate. The solvent was then removed by evaporation under reducedpressure. The residue was purified by silica gel column chromatographyusing a 1:1 by volume mixture of ethyl acetate and hexane as the eluent,and the product was recrystallized from a mixture of ethyl acetate andhexane, to afford 0.14 g of the title compound as pale brown needle-likecrystals, melting at 205° to 208° C.

Elemental analysis: Calculated for C₁₀ H₉ N₃ S C, 59.09%; H, 4.46%; N,20.67%; S, 15.77%. Found: C, 59.12%; H, 4.49%; N, 20.52%; S, 16.06%.

EXAMPLE 22 6-(2-Furyl)-1H-imidazo[1,2-b]pyrazole

A solution of 2.0 g of 5-(2-furyl)-3-aminopyrazole in 5 ml ofdimethylformamide was slowly added dropwise at room temperature, whilststirring, to 0.59 g of a 55% w/w suspension of sodium hydride in mineraloil, which itself was suspended in 15 ml of dimethylformamide, and theresulting mixture was stirred for 1 hour at room temperature. 2.7 g of2,2-dimethoxyethyl bromide were then added, and the mixture was allowedto react at 60° to 70° C. for 4 hours. At the end of this time, theresulting mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was then removed by evaporation under reducedpressure. The residue was purified by silica gel column chromatographyusing a 1:1 by volume mixture of ethyl acetate and hexane as the eluent,to afford 1.2 g of an intermediate compound as an oil.

A mixture of 1.2 g of this intermediate compound, 10 ml of a 4N solutionof hydrogen chloride in dioxane and 4 ml of ethanol was heated underreflux for 20 minutes, after which the reaction mixture was poured intoice water and made basic by the addition of aqueous ammonia. The mixturewas then extracted with ethyl acetate. The extract was washed with anaqueous solution of sodium chloride and dried over anhydrous magnesiumsulfate, after which the solvent was removed by evaporation underreduced pressure. The residue was purified by silica gel columnchromatography using a 1:1 by volume mixture of ethyl acetate and hexaneas the eluent, and the product was recrystallized from a mixture ofethyl acetate and hexane, to afford 0.44 g of the title compound as palebrown needle-like crystals, melting at 186° to 188° C.

Elemental analysis: Calculated for C₉ H₇ N₃ O: C, 62.42%; C, 4.07%; N,24.27%. Found: C, 62.36%; H, 4.23%; N, 24.14%.

EXAMPLES 23 TO 25

The following compounds were synthesized in the same manner as describedin Examples 20 to 22.

                  TABLE 4                                                         ______________________________________                                        Example       Compound                                                        No.           No.       m.p. (°C.)                                     ______________________________________                                        23            59        230 to 235                                            24            58        167 to 169                                            25            65        205 to 208                                            ______________________________________                                    

EXAMPLE 26 1-Ethyl-6-(3-trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazolehydrochloride

800 mg of 6-(3-trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazole and 5 mlof dimethylformamide were slowly added dropwise at room temperature,whilst stirring, to 76 mg of a 55% w/w suspension of sodium hydride inmineral oil, which was itself suspended in 10 ml of dimethylformamide,and the resulting mixture was stirred for 30 minutes at roomtemperature. 497 mg of ethyl bromide were then added dropwise, whilstcooling with ice water, and the resulting mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was then partitionedbetween ethyl acetate and water. The ethyl acetate layer was washed withwater and with an aqueous solution of sodium chloride, in that order,and dried over anhydrous magnesium sulfate. The solvent was then removedby evaporation under reduced pressure. The product was then purified bysilica gel column chromatography using a 1:1 by volume mixture of ethylacetate and hexane as the eluent, to afford the title compound as anoil. The hydrochloride was formed from this oil by adding a 4N solutionof hydrogen chloride in dioxane, and this was recrystallized from amixture of acetone and diethyl ether, to afford 750 mg of1-ethyl-6-(3-trifluoromethylphenyl)-1H-imidazo[1,2-b]pyrazolehydrochloride as pale brown prismatic crystals, melting at 135° to 141°C.

Elemental analysis: Calculated for C₁₄ H₁₃ N₃ ClF₃ : C, 53.26%; H,4.15%; N, 13.31%; Cl, 11.23%; F, 18.05%. Found: C, 53.18%; H, 4.21%; N,13.32%; Cl, 11.28%; F, 18.00%.

EXAMPLES 27 AND 28

The compounds shown in Table 5 were also prepared by the methoddescribed in Example 26.

                  TABLE 5                                                         ______________________________________                                        Ex. No.     Compound No.  m.p. (°C.)                                   ______________________________________                                        27          197 (hydrochloride)                                                                         185-187                                             28          198           125-127                                             ______________________________________                                    

EXAMPLE 29 7-Phenyl-1H-imidazo[1.2-b]pyrazole (Compound No. 41)

A solution of 2.0 g of 3-amino-4-phenylpyrazole in 10 ml ofdimethylformamide was slowly added dropwise, whilst stirring at roomtemperature, to 0.55 g of a 55% by weight suspension of sodium hydridein mineral oil, which itself was suspended in 20 ml ofdimethylformamide. The mixture was then stirred for 1 hour at roomtemperature, after which 1.8 ml of 2,2-dimethoxyethyl bromide was added,and then the whole mixture was stirred at 60°-70° C. for 4 hours. At theend of this time, the reaction mixture was partitioned between water andethyl acetate. The organic phase was washed with water and dried overanhydrous magnesium sulfate. The solvent was then removed by evaporationunder reduced pressure, to leave a residue, which was purified by columnchromatography through silica gel, eluted with a 1:1 by volume mixtureof ethyl acetate and hexane, to give 0.45 g of an intermediate compoundas an oil.

A mixture of the whole of this oil, 5 ml of 4N hydrogen chloride indioxane and 2 ml of ethanol was heated under reflux for 30 minutes. Atthe end of this time, the reaction mixture was poured into ice-water andmade alkaline by the addition of aqueous ammonia. The mixture was thenextracted with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride and dried over anhydrous magnesium sulfate.The solvent was then distilled off under reduced pressure, and theresidue was purified first by silica gel column chromatography using a1:1 by volume mixture of ethyl acetate and hexane as the eluent, andthen by recrystallization from a mixture of ethyl acetate and hexane, togive 0.2 g of the title compound in the form of colorless needlesmelting at 212°-214° C.

Elemental Analysis: Calculated for C₁₁ H₉ N₃ : C, 72.11%; H, 4.95%; N,22.94%. Found: C, 71.86%; H, 5.18%; N, 22.83%.

EXAMPLES 30 TO 53

Following substantially the same procedure as that described in Example29, the following compounds were obtained.

                  TABLE 6                                                         ______________________________________                                        Example No.   Compound No.                                                                              m.p. (°C.)                                   ______________________________________                                        30             76         164-166                                             31             80         164-166                                             32            140         181-182                                             33            100         >230                                                34            101         220-224                                             35            108         210-212                                             36            109         231-233                                             37             93         190-191                                             38             97         185-187                                             39            114         204-205                                             40            115         178-180                                             41            170         144-145                                             42             90         >260                                                43             92         205-207                                             44            104         214-216                                             45            106         180-182                                             46            117         186-187                                             47            119         194-195                                             48            123         193-196                                             49            124         >250                                                50            125         >250                                                51            141         178-180                                             52            167         192-194                                             53            168         176-178                                             ______________________________________                                    

EXAMPLE 542-Ethoxycarbonylmethyl-7-methyl-6-phenyl-1H-imidazo-[1,2-b]pyrazole(Compound No. 38)

0.78 ml of ethyl 4-chloroacetoacetate was added to a solution of 1.0 gof 3-amino-4-methyl-5-phenyl-1H-pyrazole in 25 ml of acetonitrile, andthen the mixture was stirred at room temperature for 4 days. At the endof this time, the crystals which separated were filtered off and themother liquor was concentrated by evaporation under reduced pressure.The residue was partitioned between ethyl acetate and water, and theorganic phase was washed with water and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography through silica gel, usinga 1:1 by volume mixture of ethyl acetate and hexane as the eluent, togive 80 mg of the title compound in the form of an oil.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.20 (3H, triplet,J=8.0 Hz); 2.15 (3H, singlet); 3.60 (2H, singlet) 4.15 (2H, quartet,J=8.0 Hz); 7.15 (1H, singlet); 7.2-7.8 (5H, multiplet).

EXAMPLE 55 1-Ethoxycarbonylmethyl-6-phenylimidazo[1,2-b]-pyrazole(Compound No. 190)

A solution of 0.4 g of 6-phenyl-1H-imidazo[1,2-b]-pyrazole in 10 ml ofdimethylformamide was slowly added dropwise, whilst stirring at roomtemperature, to 96 mg of a 55% w/w suspension of sodium hydride inmineral oil, which was itself suspended in 10 ml of dimethylformamide,and then the mixture was stirred for a further 1 hour. At the end ofthis time, 0.24 ml of ethyl bromoacetate and 10 ml of dimethylformamidewere added, and then the whole mixture was stirred at room temperaturefor 3 hours. The reaction mixture was then partitioned between ethylacetate and water, and then the organic phase was washed with water anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified first by columnchromatography through silica gel, eluted with a 1:1 by volume mixtureof ethyl acetate and hexane, and then by recrystallization from amixture of ethyl acetate and hexane, to give 0.38 g of the titlecompound in the form of plates melting at 85°-87° C.

Elemental Analysis: Calculated for C₁₅ H₁₅ N₃ O₂ : C, 66.90%; H, 5.61%;N, 15.60%; O, 11.89%. Found: C, 66.61%; H, 5.66%; N, 15.70%; O, 12.03%.

EXAMPLES 56 AND 57

Following substantially the same procedure as that described in Example55, the following compounds were obtained.

                  TABLE 7                                                         ______________________________________                                        Example No.   Compound No.                                                                              m.p. (°C.)                                   ______________________________________                                        56            206         70-75                                               57            191          117-119.                                           ______________________________________                                    

EXAMPLE 58 7-(4-Methylphenyl)-6-methyl-1H-imidazo[1,2-]pyrazole(Compound No. 109)

A mixture of 1.7 g of 2-(4-methylphenyl)-3-oxo-butyronitrile, 20 ml ofethanol and 1.5 g of 2,2-diethoxyethylhydrazine was heated under refluxfor 7 hours. At the end of this time, 30 ml of 4N hydrogen chloride indioxane were added, and then the whole mixture was heated under refluxfor a further 30 minutes. After the mixture had been cooled, diethylether was added to precipitate crystals. These were collected byfiltration and partitioned between ethyl acetate and dilute aqueousammonia. The organic phase was separated, washed with water and driedover anhydrous magnesium sulfate. The solvent was then removed bydistillation under reduced pressure, to leave a residue, which wasrecrystallized from a mixture of ethyl acetate and hexane, to give 1.5 gof the title compound. The physical and chemical properties of thiscompound were the same as those of the compound prepared as described inExample 36.

EXAMPLES 59 to 61

The following compounds were also prepared by a procedure similar tothat described in Example 58.

                  TABLE 8                                                         ______________________________________                                        Ex. No.     Compound No.  m.p. (°C.)                                   ______________________________________                                        59          193 (hydrochloride)                                                                         232-235                                             60          195           208-210                                             61          204 (hydrochloride)                                                                         205-207                                             ______________________________________                                    

EXAMPLE 62 7-(4-Aminophenyl)-6-methyl-1H-imidazo[1,2-b]-pyrazolehydrochloride

A mixture of 2.5 g of2-(4-t-butoxycarbonylaminophenyl)-3-oxobutyronitrile, 20 ml of ethanoland 1.4 g of 2,2-diethoxyethylhydrazine was heated under reflux for 2hours. 20 ml of 4N hydrogen chloride in dioxane were added, and then thewhole mixture was heated under reflux for a further 30 minutes. Afterthe mixture had been cooled, ethyl acetate was added to precipitatecrystals. These crystals were collected by filtration and recrystallizedfrom ethanol to give 1.4 g of the title compound as pale brown platesmelting at 180°-190° C.

EXAMPLE 63

    ______________________________________                                        Tablet                                                                        ______________________________________                                        The following components were mixed:                                          Compound of Example 35    50     mg                                           Corn starch               40     mg                                           Lactose                   105    mg                                           HPC (produced by Nippon Soda)                                                                           4      mg                                           Magnesium stearate        1      mg                                           Total:                    200    mg                                           ______________________________________                                    

The mixture was then formed by conventional means into tablets, eachcontaining 200 mg of the above mixture.

EXAMPLE 64

    ______________________________________                                        Capsule                                                                       ______________________________________                                        The following components were mixed:                                          Compound of Example 4     100    mg                                           Corn starch               70     mg                                           Lactose                   168.3  mg                                           Magnesium stearate        1.7    mg                                           Total:                    340.0  mg                                           ______________________________________                                    

The mixed powders were then passed through a 20 mesh (Tyler standardmesh) sieve, and packed into No. 2 gelatin capsules, 340 mg of powderper capsule.

BIOLOGICAL ACTIVITY

The following tests were conducted to determine the activity andtoxicity of the compounds of the present invention. The drugs were alladministered orally.

1. Anti-inflammatory effect Carrageenan edema method

The percent inhibition against carrageenan-induced edema in rats of theWistar strain, using the conventional method of C. A. Winter, E. A.Risley, G. W. Nuss [J. Pharmacol., Exp. Therap., 141, 369 (1963)].Except where otherwise noted, the dose of test compound was 50 mg/kg.The results are reported in Table 9.

2. Anti-inflammatory effect Reversed passive alusas reaction

The test animals were rats of the Sprague-Dawley strain, which had firstbeen fasted for 17 hours. The hair was trimmed from their dorsalportions by means of a hair clipper, and 0.1 ml/site of anti-rat IgGrabbit serum was injected intracutaneously at the trimmed part to induceinflammation. Except in the case of the control animals, to which noanti-inflammatory drug was administered, the test drug was administeredorally immediately before inflammation was induced. Except whereotherwise noted, the dose of test compound was 50 mg/kg. Two hours afterinduction of inflammation, a 1% by volume solution of Evans blue inphysiological saline was injected intravenously into the tail of eachrat in an amount of 1 ml per each animal. 30 minutes after thisinjection, the rats were sacrificed with carbon dioxide and their skinswere peeled off to extract the chromogen of the blue spots. In moredetail, the skins were cut into small pieces and extracted with 5 ml anextraction solvent at room temperature for 2 days. The supernatantobtained by centrifugation was then measured spectrophotometrically atan absorption wavelength of 605 nm. The percent inhibition ofinflammation of the group of rats to which the test drug wasadministered was determined relative to the control group. The resultsare also reported in Table 9.

3. Analgesic effect

These tests were conducted according to the Randall-Selitto method usingrats of the Wistar strain [L. O. Randall, J. J. Selitto: Arch. int.Pharmacodyn. 111, 409 (1957)]. Except where otherwise noted, the dose oftest compound was 50 mg/kg. The results are also reported in Table 9.

4. Acute toxicity

The test animals employed were male mice of the ddy strain (age: 5weeks). A suspension of the drug in a 0.5% by volume carboxymethylcellulose solution was orally administered, and the animals wereobserved for 7 days. The dose of test compound was 300 mg/kg. Theresults are also reported in Table 9.

                  TABLE 9                                                         ______________________________________                                                          Anti-                                                       Cpd.  Anti-       inflammatory                                                                              Analgesic                                       of    inflammatory                                                                              effect      effect                                          Ex.   effect      (Reversed   (Randall-                                                                             Toxicity                                No.   (Carrageenan)                                                                             passive alusas)                                                                           Selitto)                                                                              (mouse)                                 ______________________________________                                        1     44.2%       --          4/5     0/3                                     2     54.0%       69.6%       3/5     0/3                                     3     65.1%       88.0%       5/5     0/5                                     5     64.9%       60.5%       5/5     0/5                                     5     53.7%       67.6%       5/5     0/3                                     8     76.5%       74.7%       5/5     0/3                                     10    51.3%       56.3%       5/5     0/3                                     20    89.3%       79.6%       5/5     0/3                                     21    53.4%        78.1%*     5/5     0/3                                     22    76.3%       --           4/5*   0/3                                     24    71.9%       --           4/5*   0/3                                     29    63.2%*       72.2%*      5/5*   0/3                                     30    50.0%*      --           5/5*   0/3                                     32    54.7%*       82.5%*      5/5*   0/3                                     35    56.4%*       69.9%*      5/5*   0.3                                     ______________________________________                                         *The dose was 25 mg/kg.                                                  

The results of the above tests are also reported below, in terms of theID₅₀ (anti-inflammatory tests) or ED₅₀ (analgesic test). The tests werealso carried out using certain compounds of the prior art, and theseresults are reported in the following Table 10. The prior art compoundsemployed were Benzydamine (Merck Index, 10th Edition, Monograph No.1128) and Mepirizole, whose systematic name is3-methoxy-1-(4-methoxy-6-methylpyrimidin-2-yl)-5-methylpyrazole.

                  TABLE 10                                                        ______________________________________                                                              Anti-                                                   Cpd.      Anti-       inflammatory                                                                              Analgesic                                   of        inflammatory                                                                              reversed    Randall-                                    Ex.       Carrageenan passive alusas                                                                            Selitto                                     No.       (mg/kg)     (mg/kg)     (mg/kg)                                     ______________________________________                                         3        36.6        13.9        6.1                                          4        34.1        26.7        2.4                                         20        17.1         7.0        8.0                                         21        22.3         7.9        10.0                                        29        20.1        14.8        5.1                                         30        25.0        --          5.9                                         32        23.4        10.9        6.9                                         Benzydamine                                                                             193         --          >200                                        Mepirizole                                                                              106         --          63.9                                        ______________________________________                                    

5. 5-Lipoxygenase inhibitory activity

The preparation of polymorphonuclear leukocytes was carried out by themethod of Sbarra et al [Sbarra A. J. and Karnovsky, M. L.; J. Biol.Chem., 234, 1355-1362 (1959)]. Specifically, a 2% w/v aqueous caseinsolution was administered intraperitoneally to male guinea pigs of theHartley strain, each weighing about 400-500 g. The polymorphonuclearleukocytes were harvested from the peritoneal exudate 14-16 hours afterthe administration. The preparation of enzyme was carried out by themethod of Yoshimoto et al [Yoshimoto, T., Furukawa, M., Yamamoto, S.,Horie, T. and WatanabeKohno, S.; Biochem. Biophys. Commun., 116, 612-618(1983)]. The harvested polymorphonuclear leukocytes were suspended in a50 mM phosphate buffer solution (pH=7.4) containing 10% ethylene glycoland 1 mM EDTA at a density of 1×10⁸ cells/ml. The suspension wassubjected to ultrasound twice, each time for 30 seconds at 20 KHz, andwas then centrifuged for 10 minutes at 10,000 G. The supernatant wasisolated as an enzyme fraction, which was stored at -80° C. The enzymeassay was carried out by a modification of Ochi's method [Ochi, K.,Yoshimoto, T., Yamamoto., S., Taniguchi, K. and Miyamoto, T.; J. Biol.Chem., 258, 5754-5758 (1983)]. Specifically, 2 mM CaCl₂, 1 mMglutathione, 2 mM ATP (adenosine-5'-triphosphate), 16 μM [¹⁴C]-arachidonic acid (0.16 μCi, dissolved in 5 μl ethanol), the testcompound (dissolved in 4 μl DMSO) and the enzyme solution (containing200 μg of protein) were made up to a final volume of 200 μl in a 50 mMpotassium phosphate buffer solution (pH=7.4). The test compound and theenzyme were preincubated at 30° C. for 5 minutes. After the addition ofthe arachidonic acid, the mixture was incubated at 30° C. for 30minutes. The reaction was stopped by the addition of 50 μl of 0.2Ncitric acid. The reaction mixture was then extracted with ethyl acetateand the extract was concentrated under a stream of nitrogen. Theconcentrate was subjected to thin layer chromatography and eluted with a85:15:0.1 by volume mixture of diethyl ether, petroleum ether and aceticacid. The 5-hydroxyicosatetraenoic acid (5-HITE) fraction of the platewas identified with a radioactive scanner and the radioactivity wasmeasured. The IC₅₀ (μg/ml) was calculated against the inhibitory rate ofthe production of 5-HITE of a control group, to which a test compoundwas not administered. The results are reported in Table 11.

                  TABLE 11                                                        ______________________________________                                               Test compound                                                                 Cpd. of Ex. No.                                                                         IC.sub.50                                                    ______________________________________                                               10        1.1                                                                 11        2.0                                                                 12        0.94                                                                41        0.66                                                                30        0.50                                                         ______________________________________                                    

The results of this test demonstrate that the compounds of the presentinvention have the ability to inhibit the activity of 5-lipoxygenase. Acorrelation between the inhibition of 5-lipoxygenase and anti-allergicactivity is demonstrated by Yen, S. S. and Kreutner, W.; Agents andActions, 10, 274-278 (1980), and Nijkamp, F. P. and Ramakers, A. G. M.;Europ. J. Pharmacol., 62, 121-122 (1980).

As can be seen from the results of the above tests, the compounds of thepresent invention have anti-inflammatory, analgesic and antipyreticactivities, and are thus expected to be useful as therapeutic agents forimproving and treating chronic articular rheumatism, lumbago,neck-shoulder-arm syndrome, etc.

6. Anti-ulcer activity

Suppression of gastric acid secretions was tested in rats by the Shaymethod [H. Shay; Gastroenterology, 5, 43 (1945)]. The results arereported in the following Table 12, which shows that the compounds ofthe present invention strongly suppressed gastric acid secretion,comparing well with a known anti-ulcer drug, cimetidine. Therefore, thecompounds of the present invention are expected to have some anti-ulceractivity. This is all the more surprising since compounds havinganalgesic and anti-inflammatory activities are commonly known to causeulcers, rather than to cure them.

                  TABLE 12                                                        ______________________________________                                        Cpd of      Dosage                                                            Ex. No.     (mg/kg - i.d.)                                                                           Suppression rate (%)                                   ______________________________________                                        3           10         66                                                     3           30         85                                                     4           10         67                                                     4           30         100                                                    20          10         84                                                     20          30         93                                                     Cimetidine  10         62                                                     Cimetidine  30         58                                                     ______________________________________                                    

As can be seen from the results of the above tests, the compounds of thepresent invention have anti-inflammatory, analgesic, antipyretic andanti-ulcer activities, and are thus expected to be useful as therapeuticagents for improving and treating chronic articular rheumatism, lumbago,neck-shoulder-arm syndrome, etc.

We claim:
 1. A method of relieving or alleviating allergic reactions bythe administration to a mammal suffering from said allergic reactions ofan effective amount of an inhibitor of 5-lipoxygenase, wherein saidinhibitor is selected from the group consisting of compounds of formula(I): ##STR10## in which: R¹ and R² are independently selected from thegroup consisting of: hydrogen atoms; C₁ -C₁₁ alkyl groups: substitutedC₁ -C₆ alkyl groups having at least one substituent selected from thegroup consisting of substituents (a¹), defined below: C₃ -C₆ cycloalkylgroups: C₂ -C₆ alkenyl groups: aralkyl groups in which the alkyl part isC₁ -C₄ and the aryl part is a phenyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b¹), defined below: phenylalkenyl groups in which thephenyl part is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (b¹), defined below, and thealkenyl part is C₂ -C₃ alkenyl: C₆ -C₁₀ aryl groups: C₆ -C₁₀ aryl groupshaving at least one substituent selected from the group consisting ofsubstituents (b¹), defined below: and halogen atoms;R³ represents: ahydrogen atom; a C₁ -C₂₅ alkyl group; a substituted C₁ -C₆ alkyl grouphaving at least one substituent selected from the group consisting ofsubstituents (a), defined below; an aralkyl group in which the alkylpart is C₁ -C₄ and the aryl part is C₆ -C₁₀ and is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b), defined below; a C₁ -C₆ aliphatic carboxylic acylgroup; or an aromatic carboxylic acyl group in which the aryl part is aC₆ -C₁₀ carbocyclic aryl group which is unsubstituted or has at leastone substituent selected from the group consisting of substituents (b),defined below; R⁴ and R⁵ are independently selected from the groupconsisting of: hydrogen atoms: C₁ -C₂₅ alkyl groups; substituted C₁ -C₆alkyl groups having at least one substituent selected from the groupconsisting of substituents (a), defined below: C₃ -C₈ cycloalkyl groups:C₂ -C₆ alkenyl groups; aralkyl groups in which the alkyl part is C₁ -C₄and the aryl part is C₆ -C₁₀ and is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b),defined below; arylalkenyl groups in which the aryl part is a C₆ -C₁₀aryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (b), defined below,and the alkenyl part is C₂ -C₃ alkenyl: C₆ -C₁₀ aryl groups; and C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b), defined below: substituents (a):hydroxygroups, halogen atoms, carboxy groups, cyano groups, C₂ -C₇alkoxycarbonyl groups; substituents (b):C₁ -C₆ alkyl groups; halogenatoms; C₁ -C₆ alkoxy groups; aryloxy groups in which the aryl part is anunsubstituted C₆ -C₁₀ carbocyclic aryl group; aralkyloxy groups in whichthe alkyl part is C₁ -C₄ and the aryl part is C₆ -C₁₀ and isunsubstituted; C₁ -C₆ aliphatic carboxylic acyl groups; aromaticcarboxylic acyl groups in which the aryl part is a C₆ -C₁₀ carbocyclicaryl group which is unsubstituted or has at least one substituentselected from the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxygroups and halogen atoms; C₁ -C₆ aliphatic carboxylic acyloxy groups;aromatic carboxylic acyloxy groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; amino groups; C₁ -C.sub. 4alkylamino groups; dialkylamino groups in which each alkyl part is C₁-C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; aromatic carboxylicacylamino groups in which the aryl part is a C₆ -C₁₀ carbocyclic arylgroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms; C₁ -C₄ haloalkyl groups; carbamoyl groups;alkylcarbamoyl and dialkylcarbamoyl groups in which the or each alkylgroup is C₁ -C₄ ; carboxy groups; hydroxy groups; cyano groups; and C₂-C₇ alkoxycarbonyl groups substituents (a¹):hydroxy groups, halogenatoms, carboxy groups, cyano groups, and C₂ -C₄ alkoxycarbonyl groupssubstituents (b¹):C₁ -C₄ alkyl groups; halogen atoms; C₁ -C₄ alkoxygroups; phenoxy groups; aralkyloxy groups in which the alkyl part is C₁-C₄ and the aryl part is an unsubstituted phenyl group; C₂ -C₆ aliphaticcarboxylic acyl groups; benzoyl groups which are unsubstituted or haveat least one substituent selected from the group consisting of C₁ -C₄alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₆ aliphaticcarboxylic acyloxy groups; benzoyloxy groups which are unsubstituted orhave at least one substituent selected from the group consisting of C₁-C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; amino groups;C₁ -C₄ alkylamino groups; dialkylamino groups in which each alkyl partis C₁ -C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; benzoylaminogroups which are unsubstituted or have at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms; C₁ -C₄ haloalkyl groups; carbamoyl groups;alkylcarbamoyl and dialkylcarbamoyl groups in which the or each alkylgroup is C₁ -C₄ ; carboxy groups; and C₂ -C₅ alkoxycarbonyl groupsandpharmaceutically acceptable salts thereof.
 2. A method of relieving oralleviating allergic reactions by the administration to a mammalsuffering from said allergic reactions of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of compounds of formula (I): ##STR11## in which: R¹ andR² are independently selected from the group consisting of: hydrogenatoms; C₁ -C₂₅ alkyl groups; substituted C₁ -C₆ alkyl groups having atleast one substituent selkected from the group consisting ofsubstituents (a), defined below; C₃ -C₈ cycloalkyl groups; C₂ -C₆alkenyl groups; aralkyl groups in which the alkyl part is C₁ -C₄ and thearyl part is C₆ -C₁₀ and is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b),defined below; arylalkenyl groups in which the aryl part is a C₆ -C₁₀aryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (b), defined below,and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b), defined below; cyano groups; and halogenatoms;R³ represents: a hydrogen atom; a C₁ -C₁₁ alkyl group; asubstituted C₁ -C₆ alkyl group having at least one substituent selectedfrom the group consisting of substituents (a¹), defined below; anaralkyl group in which the alkyl part is C₁ -C₄ and the aryl part is aphenyl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (b¹), defined below;a C₁ -C₆ aliphatic carboxylic acyl group; or a benzoyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below; R⁴ and R⁵ areindependently selected from the group consisting of: hydrogen atoms; C₁-C₂₅ alkyl groups; substituted C₁ -C₆ alkyl groups having at least onesubstituent selected from the group consisting of substituents (a),defined below; C₃ -C₈ cycloalkyl groups; C₂ -C₆ alkenyl groups; aralkylgroups in which the alkyl part is C₁ -C₄ and the aryl part is C₆ -C₁₀and is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (b), defined below; arylalkenyl groupsin which the aryl part is a C₆ -C₁₀ aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (b), defined below, and the alkenyl part is C₂ -C₃ alkenyl;C₆ -C₁₀ aryl groups; and C₆ -C₁₀ aryl groups having at least onesubstituent selected from the group consisting of substituents (b),defined below; substituents (a):hydroxy groups, halogen atoms, carboxygroups, cyano groups, C₂ -C₇ alkoxycarbonyl groups; substituents (b):C₁-C₆ alkyl groups; halogen atoms; C₁ -C₆ alkoxy groups; aryloxy groups inwhich the aryl part is an unsubstituted C₆ -C₁₀ carbocyclic aryl group;aralkyloxy groups in which the alkyl part is C₁ -C₄ and the aryl part isC₆ -C₁₀ and is unsubstituted; C₁ -C₆ aliphatic carboxylic acyl groups;aromatic carboxylic acyl groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₆ aliphatic carboxylicacyloxy groups; aromatic carboxylic acyloxy groups in which the arylpart is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted or hasat least one substituent selected from the group consisting of C₁ -C₄alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; amino groups; C₁-C.sub. 4 alkylamino groups; dialkylamino groups in which each alkylpart is C₁ -C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; aromaticcarboxylic acylamino groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₄ haloalkyl groups;carbamoyl groups; alkylcarbamoyl and dialkylcarbamoyl groups in whichthe or each alkyl group is C₁ -C₄ ; carboxy groups; hydroxy groups;cyano groups; and C₂ -C₇ alkoxycarbonyl groups substituents (a¹):hydroxygroups, halogen atoms, carboxy groups, cyano groups, and C₂ -C₄alkoxycarbonyl groups; substituents (b¹):C₁ -C₄ alkyl groups; halogenatoms; C₁ -C₄ alkoxy groups; phenoxy groups; aralkyloxy groups in whichthe alkyl part is C₁ -C₄ and the aryl part is an unsubstituted phenylgroup; C₂ -C₆ aliphatic carboxylic acyl groups; benzoyl groups which areunsubstituted or have at least one substituent selected from the groupconsisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogenatoms; C₁ -C₆ aliphatic carboxylic acyloxy groups; benzoyloxy groupswhich are unsubstituted or have at least one substituent selected fromthe group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups andhalogen atoms; amino groups; C₁ -C₄ alkylamino groups; dialkylaminogroups in which each alkyl part is C₁ -C₄ ; C₁ -C₆ aliphatic carboxylicacylamino groups; benzoylamino groups which are unsubstituted or have atleast one substituent selected from the group consisting of C₁ -C₄ alkylgroups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₄ haloalkyl groups;carbamoyl groups; alkylcarbamoyl and dialkylcarbamoyl groups in whichthe or each alkyl group is C₁ -C₄ ; carboxy groups; and C₂ -C₅alkoxycarbonyl groups;and pharmaceutically acceptable salts thereof. 3.A method of relieving or alleviating allergic reactions by theadministration to a mammal suffering from said allergic reactions of aneffective amount of an inhibitor of 5-lipoxygenase, wherein saidinhibitor is selected from the group consisting of compounds of formula(I): ##STR12## in which: R¹ and R² are independently selected from thegroup consisting of: hydrogen atoms; C₁ -C₂₅ alkyl groups; substitutedC₁ -C₆ alkyl groups having at least one substituent selected from thegroup consisting of substituents (a), defined below; C₃ -C₈ cycloalkylgroups; C₂ -C₆ alkenyl groups; aralkyl groups in which the alkyl part isC₁ -C₄ and the aryl part is C₆ -C₁₀ and is unsubstituted or has at leastone substituent selected from the group consisting of substituents (b),defined below; arylalkenyl groups in which the aryl part is a C₆ -C₁₀aryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (b), defined below,and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b), defined below; cyano groups; and halogenatoms;R³ represents: a hydrogen atom; a C₁ -C₂₅ alkyl group; asubstituted C₁ -C₆ alkyl group having at least one substituent selectedfrom the group consisting of substituents (a), defined below; an aralkylgroup in which the alkyl part is C₁ -C₄ and the aryl part is C₆ -C₁₀ andis unsubstituted or has at least one substituent selected from the groupconsisting of substituents (b), defined below; a C₁ -C₆ aliphaticcarboxylic acyl group; or an aromatic carboxylic acyl group in which thearyl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (b), defined below; R⁴ and R⁵ are independently selectedfrom the group consisting of: hydrogen atoms; C₁ -C₁₁ alkyl groups;substituted C₁ -C₆ alkyl groups having at least one substituent selectedfrom the group consisting of substituents (a¹), defined below; C₃ -C₆cycloalkyl groups; C₂ -C₆ alkenyl groups; aralkyl groups in which thealkyl part is C₁ -C₄ and the aryl part is a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below; phenylalkenyl groups inwhich the phenyl part is unsubstituted or has at least one substituentselected from the group consisting of substituents (b¹), defined below,and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; and C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b¹), defined below; substituents (a):hydroxygroups, halogen atoms, carboxy groups, cyano groups, and C₂ -C₇alkoxycarbonyl groups; substituents (b):C₁ -C₆ alkyl groups; halogenatoms; C₁ -C₆ alkoxy groups; aryloxy groups in which the aryl part is anunsubstituted C₆ -C₁₀ carbocyclic aryl group; aralkyloxy groups in whichthe alkyl part is C₁ -C₄ and the aryl part is C₆ -C₁₀ and isunsubstituted; C₁ -C₆ aliphatic carboxylic acyl groups; aromaticcarboxylic acyl groups in which the aryl part is a C₆ -C₁₀ carbocyclicaryl group which is unsubstituted or has at least one substituentselected from the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxygroups and halogen atoms; C₁ -C₆ aliphatic carboxylic acyloxy groups;aromatic carboxylic acyloxy groups in which the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of C₁ -C₄ alkyl groups,C₁ -C₄ alkoxy groups and halogen atoms; amino groups; C₁ -C.sub. 4alkylamino groups; dialkylamino groups in which each alkyl part is C₁-C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; aromatic carboxylicacylamino groups in which the aryl part is a C₆ -C₁₀ carbocyclic arylgroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms; C₁ -C₄ haloalkyl groups; carbamoyl groups;alkylcarbamoyl and dialkylcarbamoyl groups in which the or each alkylgroup is C₁ -C₄ ; carboxy groups; hydroxy groups; cyano groups; and C₂-C₇ alkoxycarbonyl groups substituents (a¹):hydroxy groups, halogenatoms, carboxy groups, cyano groups, and C₂ -C₄ alkoxycarbonyl groups;substituents (b¹):C₁ -C₄ alkyl groups; halogen atoms; C₁ -C₄ alkoxygroups; phenoxy groups; aralkyloxy groups in which the alkyl part is C₁-C₄ and the aryl part is an unsubstituted phenyl group; C₂ -C₆ aliphaticcarboxylic acyl groups; benzoyl groups which are unsubstituted or haveat least one substituent selected from the group consisting of C₁ -C₄alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₆ aliphaticcarboxylic acyloxy groups; benzoyloxy groups which are unsubstituted orhave at least one substituent selected from the group consisting of C₁-C₄ alkyl groups, C₁ -C₄ alkoxy groups and halogen atoms; amino groups;C₁ -C₄ alkylamino groups; dialkylamino groups in which each alkyl partis C₁ -C₄ ; C₁ -C₆ aliphatic carboxylic acylamino groups; benzoylaminogroups which are unsubstituted or have at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms; C₁ -C₄ haloalkyl groups; carbamoyl groups;alkylcarbamoyl and dialkylcarbamoyl groups in which the or each alkylgroup is C₁ -C₄ ; carboxy groups; and C₂ -C₅ alkoxycarbonyl groups;andpharmaceutically acceptable salts thereof.
 4. The method of claim 1,wherein:R¹ and R² are independently selected from the group consistingof: hydrogen atoms; C₁ -C₁₁ alkyl groups; substituted C₁ -C₆ alkylgroups having at least one substituent selected from the groupconsisting of substituents (a¹), defined below; C₃ -C₆ cycloalkylgroups; C₂ -C₆ alkenyl groups; aralkyl groups in which the alkyl part isC₁ -C₄ and the aryl part is a phenyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b¹), defined below; phenylalkenyl groups in which thephenyl part is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (b¹), defined below, and thealkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; C₆ -C₁₀ aryl groupshaving at least one substituent selected from the group consisting ofsubstituents (b¹), defined below; and halogen atoms; R³ represents: ahydrogen atom; a C₁ -C₁₁ alkyl group; a substituted C₁ -C₆ alkyl grouphaving at least one substituent selected from the group consisting ofsubstituents (a¹), defined below; an aralkyl group in which the alkylpart is C₁ -C₄ and the aryl part is a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below; a C₁ -C₆ aliphaticcarboxylic acyl group; or a benzoyl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (b¹), defined below; R⁴ and R⁵ are independently selectedfrom the group consisting of: hydrogen atoms; C₁ -C₁₁ alkyl groups;substituted C₁ -C₆ alkyl groups having at least one substituent selectedfrom the group consisting of substituents (a¹), defined below; C₃ -C₆cycloalkyl groups; C₂ -C₆ alkenyl groups; aralkyl groups in which thealkyl part is C₁ -C₄ and the aryl part is a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (b¹), defined below; phenylalkenyl groups inwhich the phenyl part is unsubstituted or has at least one substituentselected from the group consisting of substituents (b¹), defined below,and the alkenyl part is C₂ -C₃ alkenyl; C₆ -C₁₀ aryl groups; and C₆ -C₁₀aryl groups having at least one substituent selected from the groupconsisting of substituents (b¹), defined below; substituents(a¹):hydroxy groups, halogen atoms, carboxy groups, cyano groups, and C₂-C₄ alkoxycarbonyl groups; substituents (b¹):C₁ -C₄ alkyl groups;halogen atoms; C₁ -C₄ alkoxy groups; phenoxy groups; aralkyloxy groupsin which the alkyl part is C₁ -C₄ and the aryl part is an unsubstitutedphenyl group; C₂ -C₆ aliphatic carboxylic acyl groups; benzoyl groupswhich are unsubstituted or have at least one substituent selected fromthe group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groups andhalogen atoms; C₁ -C₆ aliphatic carboxylic acyloxy groups; benzoyloxygroups which are unsubstituted or have at least one substituent selectedfrom the group consisting of C₁ -C₄ alkyl groups, C₁ -C₄ alkoxy groupsand halogen atoms; amino groups; C₁ -C₄ alkylamino groups; dialkylaminogroups in which each alkyl part is C₁ -C₄ ; C₁ -C₆ aliphatic carboxylicacylamino groups; benzoylamino groups which are unsubstituted or have atleast one substituent selected from the group consisting of C₁ -C₄ alkylgroups, C₁ -C₄ alkoxy groups and halogen atoms; C₁ -C₄ haloalkyl groups;carbamoyl groups; alkylcarbamoyl and dialkylcarbamoyl groups in whichthe or each alkyl group is C₁ -C₄ ; carboxy groups; and C₂ -C₅alkoxycarbonyl groups.
 5. The method of claim 1, wherein:R¹ and R² areindependently selected from the group consisting of: hydrogen atoms; C₁-C₆ alkyl groups; substituted C₁ -C₄ alkyl groups having at least onesubstituent selected from the group consisting of substituents (a²),defined below; benzyl groups in which the phenyl part is unsubstitutedor has at least one substituent selected from the group consisting ofsubstituents (b²), defined below; cinnamyl groups; phenyl groups;naphthyl groups; phenyl or naphthyl groups having at least onesubstituent selected from the group consisting of substituents (b²),defined below; and halogen atoms; R³ represents: a hydrogen atom; a C₁-C₆ alkyl group; a substituted C₁ -C₄ alkyl group having at least onesubstituent selected from the group consisting of substituents (a²),defined below; a benzyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b²),defined below; a C₂ -C₄ aliphatic carboxylic acyl group; or a benzoylgroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (b²), defined below; R⁴ and R⁵are independently selected from the group consisting of: hydrogen atoms;C₁ -C₆ alkyl groups; substituted C₁ -C₄ alkyl groups having at least onesubstituent selected from the group consisting of substituents (a²),defined below; benzyl groups which are unsubstituted or have at leastone substituent selected from the group consisting of substituents (b²),defined below; cinnamyl groups; phenyl groups; naphthyl groups; andphenyl or naphthyl groups having at least one substituent selected fromthe group consisting of substituents (b²), defined below; substituents(a²): hydroxy groups, halogen atoms, cyano groups, carboxy groups, andC₂ -C₄ alkoxycarbonyl groups; substituents (b²): C₁ -C₄ alkyl groups;halogen atoms; C₁ -C₄ alkoxy groups; trifluoromethyl groups; hydroxygroups; cyano groups; amino groups; carbamoyl groups; phenoxy groups; C₂-C₆ aliphatic carboxylic acyl groups; benzoyl groups which areunsubstituted or have at least one substituent selected from the groupconsisting of C₁ -C₂ alkyl groups, C₁ -C₂ alkoxy groups and halogenatoms; C₂ -C₄ aliphatic carboxylic acyloxy groups; benzoyloxy groupswhich are unsubstituted or have at least one substituent selected fromthe group consisting of C₁ -C₂ alkyl groups, C₁ -C₂ alkoxy groups andhalogen atoms; carboxy groups; and C₂ -C₅ alkoxycarbonyl groups.
 6. Themethod of claim 5, wherein:R¹ represents a hydrogen atom or a C₁ -C₆alkyl group; R² represents: a phenyl group; a substituted phenyl grouphaving at least one substituent selected from the group consisting ofsubstituents (b²), defined above; R³ represents; a hydrogen atom; a C₁-C₄ alkyl group; a substituted C₁ -C₄ alkyl group having at least onesubstituent selected from the group consisting of substituents (a²),defined above; a C₂ -C₄ aliphatic carboxylic acyl group; or a benzoylgroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (b²), defined below; R⁴ and R⁵are independently selected from the group consisting of: hydrogen atoms;C₁ -C₆ alkyl groups; and substituted C₁ -C₄ alkyl groups having at leastone substituent selected from the group consisting of substituents (a²),defined above.
 7. The method of claim 5, wherein:R¹ represents: a phenylgroup; a substituted phenyl group having at least one substituentselected from the group consisting of substituents (b²), defined above;R² represents a hydrogen atom or a C₁ -C₆ alkyl group; R³ represents: ahydrogen atom; a C₁ -C₄ alkyl group; a substituted C₁ -C₄ alkyl grouphaving at least one substituent selected from the group consisting ofsubstituents (a²), defined above; a C₂ -C₄ aliphatic carboxylic acylgroup; or a benzoyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (b²),defined below; R⁴ and R⁵ are independently selected from the groupconsisting of: hydrogen atoms; C₁ -C₆ alkyl groups; and substituted C₁-C₄ alkyl groups having at least one substituent selected from the groupconsisting of substituents (a²), defined above.
 8. A method of relievingor alleviating allergic reactions by the administration to a mammalsuffering from said allergic reactions of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of compounds of formula (I): ##STR13## in which: R¹represents a hydrogen atom or a methyl or ethyl group:R² represents: aphenyl group; a substituted phenyl group having at least one substituentselected from the group consisting of methyl groups, chlorine atoms,trifluoromethyl groups and methoxy groups; a thienyl group; a furylgroup; or a thienyl or furyl group having at least one substituentselected from the group consisting of methyl groups, methoxy groups,chlorine atoms and trifluoromethyl groups; R³ represents: a hydrogenatom; a C₁ -C₂ alkyl group; a C₂ -C₄ aliphatic carboxylic acyl group; abenzyl group; a cyanomethyl group; a (C₁ -C₄ alkoxy)carbonylmethylgroup; or a benzoyl group; R⁴ and R⁵ are independently selected from thegroup consisting of: hydrogen atoms; C₁ -C₂ alkyl groups; andsubstituted C₁ -C₂ alkyl groups having at least one substituent selectedfrom the group consisting of C₂ -C₃ alkoxycarbonyl groupsandpharmaceutically acceptable salts thereof.
 9. A method of relieving oralleviating allergic reactions by the administration to a mammalsuffering from said allergic reactions of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of compounds of formula (I): ##STR14## in which: R¹represents: a phenyl group; a substituted phenyl group having at leastone substituent selected from the group consisting of methyl groups,chlorine atoms, trifluoromethyl groups and methoxy groups; a thienylgroup; a furyl group; or a thienyl or furyl group having at least onesubstituent selected from the group consisting of methyl groups, methoxygroups, chlorine atoms and trifluoromethyl groups;R² represents ahydrogen atom or a methyl or ethyl group; R³ represents: a hydrogenatom; a C₁ -C₂ alkyl group; a benzyl group; a cyanomethyl group; a (C₁-C₄ alkoxy)carbonylmethyl group; a C₂ -C₄ aliphatic carboxylic acylgroup; or a benzoyl group; R⁴ and R⁵ are independently selected from thegroup consisting of: hydrogen atoms; C₁ -C₂ alkyl groups; andsubstituted C₁ -C₂ alkyl groups having at least one substituent selectedfrom the group consisting of C₂ -C₃ alkoxycarbonyl groups;andpharmaceutically acceptable salts thereof.
 10. A method of relieving oralleviating allergic reactions by the administration to a mammalsuffering from said allergic reactions of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of6-phenyl-1H-imidazo[1,2-b]pyrazole;6-(p-chlorophenyl)-1H-imidazo[1,2-b]pyrazole;7-methyl-6-phenyl-1H-imidazo[1,2-b]pyrazole;7-phenyl-1H-imidazo[1,2-b]pyrazole;6-(2-thienyl)-1H-imidazo[1,2-b]pyrazole;7-methyl-6-(2-thienyl)-1H-imidazo[1,2-b]pyrazole;6-methyl-7-phenyl-1H-imidazo[1,2-b]pyrazole;6-methyl-7-(p-chlorophenyl)-1H-imidazo[1,2-b]pyrazole;7-(p-methylphenyl)-1H-imidazo[1,2-b]pyrazole;7-(2-thienyl)-1H-imidazo[1,2-b]pyrazole;6-methyl-7-(2-thienyl)-1H-imidazo[1,2-b]pyrazole;and pharmaceuticallyacceptable salts thereof. 11.6-(p-chlorophenyl)-1H-imidazo[1,2-b]-pyrazole and pharmaceuticallyacceptable salts thereof. 12.7-methyl-6-phenyl-1H-imidazo[1,2-b]-pyrazole and pharmaceuticallyacceptable salts thereof. 13.6-methyl-7-phenyl-1H-imidazo[1,2-b]-pyrazole and pharmaceuticallyacceptable salts thereof. 14.6-methyl-7-(p-chlorophenyl)-1H-imidazo-[1,2-b]pyrazole andpharmaceutically acceptable salts thereof.
 15. A method of relieving oralleviating allergic reactions by the administration to a mammalsuffering from said allergic reactions of an effective amount of aninhibitor of 5-lipoxygenase, wherein said inhibitor is selected from thegroup consisting of7-(2-methylphenyl)-1H-imidazo[1,2-b]pyrazole and7-(3-methylphenyl)-1H-imidazo[1,2-b]pyrazole.
 16. The method of claim15, wherein the inhibitor is7-(2-methylphenyl)-1H-imidazo[1,2-b]pyrazole.
 17. The method of claim15, wherein the inhibitor is7-(3-methylphenyl)-1H-imidazo[1,2-b]pyrazole.